Mechanism and Genetic Susceptibility of Neurological Disorders (May 1, 2024)_(9819994039)_(Springer) 9789819994038, 9789819994045
123 93 8MB
English Pages [425] Year 2024
Preface
Acknowledgments
Contents
Editors and Contributors
About the Editors
Contributors
1: Neuropathology of Neurological Disorders
1.1 Introduction
1.2 Degenerative Disorders
1.2.1 Alzheimer’s Disease
1.2.1.1 Amyloid Plaques
1.2.1.2 Tau
1.2.2 Parkinson’s Disease
1.2.2.1 Susceptibility of Neurons
1.2.3 Huntington’s Disease
1.2.3.1 Basal Ganglia
1.2.3.2 Neuropathology of the Basal Ganglia
Macroscopic Changes
1.2.3.3 Mechanisms of Neuropathology
1.3 Cerebrovascular Diseases
1.3.1 Stroke
1.3.2 Traumatic Brain Injury
1.3.2.1 Concussion
1.3.2.2 Contusion
1.4 Systemic Diseases
1.4.1 Multiple Sclerosis
1.4.1.1 Neuroinflammation: Unleashing the Disruption Within the Brain
1.4.1.2 Unraveling Mechanisms Behind Primary Myelin Loss
1.4.1.3 Unveiling the Neural Injury: Axonal Impairment in Multiple Sclerosis
1.5 Conclusion
References
2: Head Trauma: Etiology, Pathophysiology, Clinical Manifestation, and Biomarkers
2.1 Introduction
2.2 Etiologies of Head Trauma
2.3 Pathophysiology of TBI
2.3.1 Primary Brain Injury and Secondary Injury
2.3.2 General Stages of Cerebral Injury After TBI
2.3.3 Cerebral Blood Flow
2.3.4 Excitotoxicity
2.3.5 Mitochondrial Dysfunction
2.3.6 ROS and Lipid Peroxidation
2.3.7 Edema
2.3.8 Neuroinflammation
2.3.9 Necrosis and Apoptosis
2.4 Clinical Manifestations of Head Trauma
2.4.1 Cephalohematoma
2.4.2 Subgaleal Hemorrhage
2.4.3 Concussion
2.4.4 Cerebral Contusion
2.4.5 Traumatic Axonal Injury
2.4.6 Skull Fractures
2.4.7 Intracranial Hematomas
2.4.7.1 Epidural Hematoma
2.4.7.2 Subdural Hematoma
2.4.7.3 Traumatic Subarachnoid Hemorrhage
2.5 Biomarkers
2.6 Future Treatments
2.7 Conclusion
References
3: Current Understanding of DNA Methylation in the Pathogenesis of Neuropathic Pain
3.1 Introduction
3.2 DNA Methylation
3.3 Histone Modification
3.4 Histone Acetylation and Deacetylation in Neuropathic Pain
3.5 DNA Methylation in Neuropathic Pain
3.6 Conclusion and Future Perspectives
References
4: Decoding Dystrophin Gene Mutations: Unraveling the Mysteries of Muscular Dystrophy
Abstract
4.1 Introduction
4.2 Cellular Roles of Dystrophin
4.3 Dystrophin-Associated Disease
4.4 DMD Gene Association with Neurological Disorders and Central Nervous System
4.5 Mutation in Dystrophin and Its Genetic Predisposition
4.5.1 Large (Deletion and Duplication) Mutations
4.5.2 Small (Point, Frameshift, Indels, Splice-Site) Mutations
4.6 Diagnosis of Muscular Dystrophy
4.7 Novel Approaches to Gene-Based Therapy: Strategies and Future Prospects
4.7.1 Stem Cell Therapy for DMD
4.7.2 CRISPR Therapeutics
4.7.3 Exon Skipping Therapy with Antisense Oligonucleotides
4.7.4 miRNAs as Serum Biomarkers
4.7.5 Genetic Counseling
4.8 Conclusion
References
5: Etiology of Ataxia: A Mechanistic Insight of Autoimmune, Toxicity, and Genetic Approach
5.1 Introduction
5.2 Categorization of Ataxias
5.2.1 Acquired Ataxias (A-At)
5.2.1.1 Paraneoplastic Cerebellar Degeneration (PCD)
5.2.1.2 Non-paraneoplastic Cerebellar Degeneration
Anti-GAD Ataxia
Gluten Ataxia
Anti-contactin-Associated Protein 2 (CASPR2) Antibody-Associated Encephalitis
Anti-metabotropic Glutamate Receptor (mGluR1) Encephalitis
5.3 Inherited/Genetic Ataxia: Etiology Focused on Genetic
5.3.1 SCAs
5.3.1.1 Insight of Molecular Mechanisms
Ataxia Associated with Polyglutamine Expansion
SCA and Channelopathies
Mitochondrial Dysfunction
Autophagy
Transcriptional Dysregulation
Genetic Modifiers
5.3.2 Autosomal Recessive Cerebellar Ataxias (ARCAs)
5.3.2.1 Underlying Pathological Mechanisms for Triggering ARCAs
Mitochondrial Defects
Nucleic Acid Maintenance and Its Quality Control
Metabolisms-Associated Dysfunction
5.3.2.2 The Common Form of ARCAs
Friedreich Ataxia (FA)
Ataxia with Isolated Vitamin E Deficiency (AVED)
Abeta Lipoproteinemia (Bassen Kornzweig Disease) (ABL)
Cayman Ataxia (CA)
Ataxia–Telangiectasia (AT)
Ataxia–Telangiectasia-Like (ATL) Disorder
Ataxia with Oculomotor Apraxia, Type 1 (AOA1)
Ataxia with Oculomotor Apraxia, Type 2 (AOA2)
Autosomal Recessive Spastic Ataxia of Charlevoix–Saguenay (ARSACS)
Infantile-Onset Spinocerebellar Ataxia (IOSCA)
Refsum’s Disease
Cerebrotendinous Xanthomatosis (CTX)
Marinesco–Sjogren Syndrome (MSS)
SeSAME Syndrome (Seizures, Sensorineural Deafness, Ataxia, Mental Retardation, and Electrolyte Imbalance)
SYNE1 Ataxia (Also Known as Autosomal Recessive (SCAR) 8, Recessive Ataxia of Beauce, Autosomal Recessive Cerebellar Ataxia, Type 1 (ARCA 1))
Coenzyme Q10 Deficiency Also Known as Autosomal Recessive Cerebellar Ataxia (ARCA)2
Posterior Column Ataxia and Retinitis Pigmentosa
Late-Onset Tay Sachs Disease (LOTSD)
Spinocerebellar Ataxia, Autosomal Recessive-13 (SCAR-13)
5.3.3 X-Linked Cerebellar Ataxia (X-CA)
5.4 Conclusion and Unresolved Questions
References
6: miRNA Dysregulation in Schizophrenia
6.1 Introduction
6.1.1 Indication of miRNA Dysregulation in Schizophrenia
6.1.1.1 Study of Cortical miRNA Expression After Mortality
6.1.1.2 Expression of Peripheral miRNAs Linked to Schizophrenia
6.2 The Central Nervous System (CNS) Is Related to miRNA Biosynthesis and Activities
6.3 Dysregulations of MiRNAs in Schizophrenia
6.3.1 Schizophrenia Is Associated with Modified Levels of miRNA
6.3.2 MiRNA Assembly Deregulation in Schizophrenia
6.3.3 Schizophrenia-Related SNPs Linked via miRNA
6.4 Mechanisms for miRNA Dysregulation in Schizophrenia
6.5 Alterations in miRNA Biogenesis
6.6 Pharmacological Impact
6.7 Perspective of miRNA Therapeutics
6.8 Conclusion
References
7: Muscular Dystrophy: Underlying Cellular and Molecular Mechanisms and Various Nanotherapeutic Approaches for Muscular Dystrophy
7.1 Introduction
7.2 Types of MD
7.2.1 Duchenne Muscular Dystrophy (DMD) (Meryon’s Disease)
7.2.2 Becker Muscular Dystrophy (BMD)
7.2.2.1 Modes of Inheritance (Including Types)
7.2.3 Myotonic Dystrophy (MD)
7.2.4 Limb-Girdle Muscular Dystrophy (LGMD)
7.2.4.1 Autosomal Dominant LGMD
7.2.4.2 Autosomal Recessive LGMD
7.2.5 Facioscapulohumeral Muscular Dystrophy (FSHD)
7.2.6 Congenital Muscular Dystrophy (CMD)
7.2.6.1 Fukuyama Congenital Muscular Dystrophy (FCMD)
7.2.6.2 Muscle Eye Brain (MEB) Disease
7.2.6.3 Walker–Warburg Syndrome (WWS)
7.2.7 Distal Muscular Dystrophy (DD)
7.2.8 Oculopharyngeal Muscular Dystrophy (OPMD)
7.2.9 Emery–Dreifuss Muscular Dystrophy (EDMD)
7.3 Cellular and Molecular Mechanisms Underlying Muscular Dystrophy
7.3.1 The Skeletal Muscle Structure
7.3.2 Neuro-Muscular Coordination for Muscle Contraction
7.3.3 Dystrophin Gene (DMD)
7.3.4 Dystrophin Protein and Dystrophin-Associated Protein Complex (DAPC)
7.3.5 Genetics and Mutations in the Human Dystrophin Gene
7.3.6 Consequences of Dystrophin Mutation
7.3.6.1 Mechanical Instability and Sarcolemma Disintegration
7.3.6.2 Abnormal nNOS-Mediated Cell Signaling
7.3.6.3 Oxidative Imbalance and Harm from Reactive Radicals
7.3.6.4 Chronic Inflammation
7.3.6.5 Dysregulation of Intracellular Calcium
7.3.6.6 Disrupted Muscle Repair
7.4 Important Diagnostic Approaches for Muscular Dystrophies
7.5 Various Treatment Strategies for MD
7.5.1 Medications
7.5.2 Therapies
7.5.3 Surgery
7.5.4 Nano-technological Approaches for MD
7.5.4.1 Targeted Drug Delivery and Genes Therapy for MD Treatment
7.5.4.2 Nano-regenerative Approaches for MD Treatment
7.6 Conclusion
References
8: Axonal Degeneration, Impaired Axonal Transport, and Synaptic Dysfunction in Motor Neuron Disorder
8.1 Historical Background
8.2 Introduction
8.3 Morphology of Neurons
8.3.1 Types of Neurons
8.4 Developmental Aspect and Regulatory Outlook in Neuronal Connections
8.5 Neuronal Signals and Synaptic Network Regulators
8.6 Mechanical Properties of Axon and Axonal Transport
8.7 Axonal Transport
8.7.1 Association of Genes in Axonal Transport
8.7.2 Transportation of Cargos and Cellular Moieties Across Axons
8.7.3 Axonal Impairment and Development of Disease
8.8 Axonal Transport Abnormalities and Related MND Pathogeneses
8.9 Conclusion
References
9: Alterations in Receptor Genes in Huntington’s Disease
9.1 Introduction
9.2 Pathogenesis of HD
9.2.1 Aggregation of Mutant Huntingtin
9.2.2 Transcriptional Dysregulation in HD
9.2.3 Epigenetic and Noncoding RNAs in HD
9.2.4 Role of Ubiquitin–Proteasome System and Autophagy–Lysosome System in HD
9.2.5 Synaptic Plasticity and Neuronal Hemostasis in HD
9.2.6 Cell-to-Cell Transmission of HD Aggregates
9.2.7 Astrocyte and Microglial Dysfunction in HD
9.3 Genetics of HD
9.3.1 Composition and Function of Wild Type of Huntingtin Gene
9.4 Function and Composition of Receptor Genes in HD
9.4.1 Role of Receptor Genes in HD
9.4.2 Receptor Genes Altered in HD
9.5 Cellular Location of HD Receptor Gene Products
9.5.1 The Expression of HD Receptor Genes in the Brain
9.5.2 The Location and Distribution of Gene Products in HD
9.6 Genetic Modifiers in HD
9.6.1 The Influence of Genetic Modifiers on HD Pathogenesis
9.6.2 Identification of Genetic Modifiers
9.7 Conclusion
References
10: Genetic Modulators in Amyotrophic Lateral Sclerosis
10.1 Introduction
10.2 Genetic Modulators
10.2.1 SOD1 Gene
10.2.2 TDP-43
10.2.3 FUS
10.2.4 C9ORF72 Gene
10.2.5 CHCHD10
10.3 Minimum Association of Genes in ALS
10.4 Pathophysiology of Disease
10.4.1 Neuroinflammation and Oxidative Stress
10.4.2 Excitotoxicity
10.4.3 Protein Homeostasis
10.4.3.1 Nucleocytoplasmic Transport Defects
10.4.4 Impaired DNA Repair
10.4.5 Vesicular Transport Defects
10.4.6 Axonal Transport Impaired
10.4.7 Oligodendrocyte Dysfunction
10.5 Various Strategies to Improve ALS
10.6 Biomarkers
10.6.1 Diagnostic Biomarkers
10.6.2 Prognostic Biomarkers
10.6.3 Pharmacodynamic Biomarkers
10.7 Conclusion
References
11: Modulators and Poststroke Behavioral Changes
11.1 Introduction
11.2 Types of Strokes
11.2.1 Ischemic Stroke
11.2.2 Transient Ischemic Stroke (TIA)
11.2.3 Hemorrhagic Stroke
11.3 Risk Factors of Stroke
11.4 Symptoms of Stroke
11.5 Modulators of Stroke
11.5.1 Neuro Modulators
11.5.1.1 Modulation by Cortical Stimulation
11.5.1.2 Modulation by Cerebellar Stimulation
11.5.1.3 Modulation by Vagal Stimulation
11.5.1.4 Modulation by Optogenetics
11.5.2 Pharmacological Modulators
11.5.2.1 Sphingosine-1-Phosphate Receptor Modulators (S1PR)
11.5.2.2 microRNAs (miRNAs)-Mediated Polarization of Microglia
11.5.2.3 microRNA-124 and microRNA-145 Modulation
11.5.2.4 d-Amphetamine
11.5.2.5 Levodopa
11.5.2.6 Sigma-1 Receptor Agonists
11.5.2.7 Fluoxetine
11.5.2.8 Niacin
11.5.2.9 Inosine
11.5.2.10 Nogo-A Inhibition
11.5.2.11 Reducing Tonic Inhibition
11.5.2.12 Phosphodiesterase 5 Inhibitors
11.6 Poststroke Physical Complications
11.7 Poststroke Cognitive Changes
11.8 Poststroke Behavioral Changes
11.8.1 Personality Changes
11.8.2 Low Self-Esteem
11.8.3 Pseudobulbar Affect
11.8.4 Attention Deficit
11.8.5 Inappropriate Behavior
11.8.6 Changes in the Libido
11.8.7 Depression
11.9 Conclusion
References
12: Presynaptic Dysfunction in Parkinson’s Disease
12.1 Introduction
12.2 Studies Used to Demonstrate Presynaptic Dysfunction in PD
12.2.1 Imaging Study
12.2.2 Pathological Study
12.2.3 PD and Synaptic Activity
12.3 Mechanisms Involved in Presynaptic Dysfunction
12.3.1 Axon Ramification on Synaptic Deprivation
12.3.2 α-Synuclein Aggregate Formation
12.3.3 Mutation of Leucine-Rich Repeat Kinase 2
12.3.3.1 Mutation of VPS35
12.3.3.2 Mutation of Synaptic Genes
12.3.4 Presence of Risk Genes
12.4 Conclusion
References
13: Mitochondrial Dysfunction and Its Role in Neurological Disorders
13.1 Introduction
13.1.1 Molecular Aspects of Mitochondrial Dysfunction
13.1.1.1 Mitochondrial DNA Mutations
13.1.1.2 Oxidative Stress and Reactive Oxygen Species (ROS)
13.1.1.3 Impaired Mitochondrial Biogenesis
13.1.1.4 Mitochondrial Dynamics
13.1.1.5 Inflammation: A Double-Edged Sword
13.1.2 Neuroinflammation
13.1.3 Role of Mitochondrial Dysfunction and Neuroinflammation
13.1.3.1 Mitochondrial Dysfunction-Induced Neuroinflammation
13.1.4 Associated Neuronal Complication with Mitochondrial Signaling Function and Neuroinflammation
13.1.5 Mitochondrial Dysfunction and Associated Diseases
13.1.5.1 Mitochondrial Dysfunction and AD
13.1.5.2 Mitochondrial Dysfunction and Parkinson’s Disease
13.1.5.3 Mitochondrial Dysfunction and Down Syndrome (DS)
13.1.5.4 Mitochondrial Dysfunction Induced Depression and Social Stress
13.1.5.5 How this Problem Can Be Overcome
References
14: Molecular and Cellular Mechanism of Pathogen Invasion into the Central Nervous System: Meningitis
14.1 Introduction
14.2 Barriers of the Central Nervous System
14.2.1 Blood-Brain Barrier
14.2.2 The Blood Cerebrospinal Fluid Barrier (BCSFB)
14.3 Bacterial Meningitis
14.3.1 Mechanism of Bacterial Meningitis
14.3.2 Neisseria Meningitidis
14.3.3 Escherichia coli
14.3.4 Streptococcus pneumoniae
14.3.5 Haemophillus influenzae Meningitis
14.3.6 Listeria monocytogenes
14.4 Viral Meningitis
14.4.1 Mechanism of Viral Meningitis
14.4.2 Epidemiology
14.4.3 Pathogenesis
14.4.3.1 Family Picornaviridae
Enteroviruses
Human Parechovirus (HPeV)
14.4.3.2 Family Herpesviridae
14.4.3.3 Family Orthomyxoviridae
14.4.4 Arboviruses
14.4.4.1 Pathophysiology
14.5 Fungal Meningitis
14.5.1 Etiology
14.6 Invasion of the CNS and Interaction with the BBB by Fungi
14.6.1 Invasion of C. neoformans into the CNS
14.7 Conclusion
References
15: Muscular Dystrophy: Mutations in the Dystrophin Gene
15.1 Introduction
15.1.1 Symptoms of MD
15.1.2 Various Types of MD
15.1.2.1 Duchenne Muscular Dystrophy (DMD)
15.1.2.2 Becker Muscular Dystrophy (BMD)
15.1.2.3 Myotonic Muscular Dystrophy (MMD)
15.1.2.4 Facioscapulohumeral Muscular Dystrophy (FSHD)
15.1.2.5 Limb-Girdle Muscle Dystrophy (LGMD)
15.1.3 Disease Mechanism
15.1.4 Mutation of Gene Dystrophin
15.1.4.1 Frameshift Mutations
15.1.4.2 In-Frame Mutation
15.1.5 Current Strategies for Muscular Dystrophy Therapeutics
15.1.5.1 Dystrophin-Targeting Strategies
Gene-Based Therapy
Drug Therapy
Cell-Based Therapy
Protein Replacement
15.1.5.2 Strategies Based on Secondary Downstream Pathological Mechanisms
Fibrosis-Targeting Strategies
Inflammation-Targeting Strategies
Strategies Based on Muscle Damage
Dysregulation of Calcium Ions
Loss of Bone Mass
15.2 Conclusion
References
16: Gene Editing Tool for Neurodegenerative Diseases
16.1 Introduction
16.1.1 Overview and Historical Background of CRISPR
16.1.1.1 CRISPR Classification and Its Components
Cas-9
Guide RNA
16.1.1.2 Molecular Mechanism of CRISPR/Cas9 System-Based Editing
16.1.1.3 CRISPR/Cas9 Gene Editing System Assisted Management and Treatment of NDs
CRISPR in Alzheimer’s Disease
CRISPR in Parkinson’s Disease
16.1.1.4 Future Perspectives in the Treatment and Management of NDs
16.2 Introduction to Zinc Finger: Gene Editing Tool
16.2.1 History and Discovery of Zing Finger
16.2.2 Structure and Function of the Zinc Finger
16.2.2.1 BTB Domain
16.2.2.2 SCAN Domain
16.2.2.3 KRAB Domain
16.2.2.4 C2H2 Zinc Finger Motif
16.2.3 Mechanism of Zinc Finger
16.2.4 The Activity of the Zinc Finger in the Brain
16.3 Other Gene Editing Tools
16.3.1 Restriction Enzymes
16.3.2 Base Editing
16.3.3 Prime Editing
16.3.4 Programmable Addition Via Site-Specific Targeting Elements (PASTE)
16.3.5 Challenges Associated with these GET’s
16.4 Transcription Activator-Like Effector Nuclease (TALEN)
16.5 Conclusion
References
17: Lumbar Disc Disease: An Overview
17.1 Introduction
17.2 History
17.2.1 Introduction of Disc Herniation Concept
17.2.2 Advancements in Surgical Treatment
17.2.3 Non-Surgical Treatment Approaches
17.2.4 Holistic Management and Practice
17.3 Epidemiology of LDS
17.4 Anatomy of the Lumbar Disc Syndrome
17.4.1 Understanding the Anatomy in Normal Conditions
17.5 Pathophysiology of LDS
17.5.1 Disc Degeneration
17.5.2 Nucleus Pulposus Herniation
17.5.3 Nerve Compression
17.5.4 Changes in Structure
17.6 The Genetic Susceptibility Associated with LDS
17.7 Types of LDS
17.7.1 Lumbar Disc Herniation
17.7.2 Lumbar Disc Degeneration
17.7.3 Lumbar Radiculopathy (Lee et al. 2020)
17.7.4 Lumbar Stenosis (Woodfield et al. 2023; Liyew 2020)
17.7.5 Cauda Equina Syndrome
17.7.6 Bulging Disc
17.8 Etiology of LDS
17.8.1 Genetics
17.8.2 Propionibacterium acnes
17.8.3 Acidic Environment
17.8.4 Spondylosis
17.8.5 Spinge Stenosis
17.8.6 Herniation of Nucleus Pulposus
17.9 Risk Factors of LDS
17.10 Management of LDS
17.11 Intervention of LDS (Wei et al. 2023; Alnafjan 2022)
17.12 Diagnostic Tools for LDS
17.12.1 Medical History and Physical Exam
17.12.2 Imaging Studies
17.13 Prevention of LDS (Din et al. 2022; Tamagawa et al. 2022)
17.14 Conclusion
References
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Andleeb Khan · Mashoque Ahmad Rather · Ghulam Md Ashraf Editors
Mechanism and Genetic Susceptibility of Neurological Disorders
Mechanism and Genetic Susceptibility of Neurological Disorders
Andleeb Khan • Mashoque Ahmad Rather Ghulam Md Ashraf Editors
Mechanism and Genetic Susceptibility of Neurological Disorders
Editors Andleeb Khan Faculty of Science Department of Biosciences Integral University Lucknow, India
Mashoque Ahmad Rather Department of Molecular Pharmacology and Physiology University of South Florida Tampa, FL, USA
Ghulam Md Ashraf Department of Medical Laboratory Sciences College of Health Sciences Sharjah Institute for Medical Research University of Sharjah Sharjah, United Arab Emirates
ISBN 978-981-99-9403-8 ISBN 978-981-99-9404-5 (eBook) https://doi.org/10.1007/978-981-99-9404-5 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Paper in this product is recyclable.
This book is dedicated to my mother (Anisun Nisa) whom we lost in 2021
Preface
Neurological disorders comprise a diverse array of medical conditions that impact the nervous system, encompassing the brain, spinal cord, and peripheral nerves. These disorders give rise to a wide spectrum of symptoms and impairments, and their origins stem from a variety of factors, including genetic predisposition, infections, autoimmune reactions, and environmental influences. Risk factors for neurological disorders are multifaceted and depend on the specific disorder in question. Nonetheless, certain general risk factors may heighten the likelihood of developing neurological conditions. These encompass age, genetic elements, environmental exposures, infections, autoimmune disorders, lifestyle factors, trauma, chronic health conditions, and psychological factors. It is important to note that not everyone with these risk factors will develop a neurological disorder, as many neurological conditions are intricate and result from multiple factors. Moreover, ongoing research continues to unveil fresh insights into the risk factors and causes of various neurological disorders, leading to advancements in prevention and treatment. Timely identification and management of these risk factors, in conjunction with a healthy lifestyle, can help mitigate the likelihood of developing neurological disorders in some cases. At present, there is no definitive cure for numerous neurological disorders, but existing therapeutic approaches can provide symptomatic relief and enhance the quality of life for patients. Today, there is a global endeavor to combat the development and progression of neurological disorders. The book titled Mechanism and Genetic Susceptibility of Neurological Disorders delves into emerging evidence regarding the genetic underpinnings of neurological disorders and their contributions to disease onset and pathology progression. This book contains a wealth of specific research updates. Esteemed researchers and scientists from around the world contribute to a thorough understanding of neurological disorders and their mechanisms. The following chapters offer an in-depth exploration of neurological disorders, shedding light on the genetic factors and molecular mechanisms involved in disease progression. The chapters within this book illuminate the mechanistic aspects of various genetic markers in the pathology of neurological disorders, emphasizing how mutations in these genetic markers drive disease progression. Additionally, the book highlights the advanced molecular techniques employed by the scientific community to investigate the multifaceted factors involved in the progression of these disorders. The compilation Mechanism and Genetic Susceptibility of Neurological Disorders is the vii
viii
Preface
most comprehensive and exhaustive work of its kind. This comprehensive compilation provides a thorough exploration of the current state of research in the field of neurological disorders and their corresponding treatment options. The editors have skillfully laid a strong groundwork for this topic, addressing the requirements of scholars and medical practitioners alike. This book serves as an invaluable resource for academics, scientists, educators, and students seeking to enhance their knowledge in this domain. Chapter 1 discusses the neuropathology, the key pathological characteristics, genetic mutations, and pathological changes associated with various neurological disorders, offering a comprehensive understanding of their underlying mechanisms. Chapter 2 provides a comprehensive overview of head trauma, including its causes, the physiological changes it induces in the brain, the observable clinical symptoms, and the potential biomarkers associated with it. Chapter 3 presents the comprehension of how DNA methylation contributes to the development and progression of neuropathic pain. Chapter 4 explores the process of deciphering mutations in the dystrophin gene, aiming to uncover the underlying complexities of muscular dystrophy. Chapter 5 provides valuable insights into understanding the causes of ataxia and its underlying mechanisms, with a focus on autoimmune, toxicological, and genetic perspectives. Chapter 6 focuses on the aberrant regulation of miRNA (microRNA) in the context of schizophrenia, aiming to shed light on its role in the disorder. Chapter 7 discusses the fundamental cellular and molecular mechanisms involved in muscular dystrophy while exploring a range of nanotherapeutic strategies for its treatment. Chapter 8 examines the processes of axonal degeneration, disrupted axonal transport, and synaptic dysfunction in motor neuron disorders, providing insight into their roles in the disease. Chapter 9 explores changes in receptor genes as they relate to Huntington’s disease, offering insights into their potential implications in the disorder. Chapter 10 investigates genetic modulators and their role in the context of Amyotrophic Lateral Sclerosis (ALS), providing insights into how genetic factors influence the disease. Chapter 11 discusses modulators and their impact on behavioral changes that occur after a stroke, shedding light on factors influencing post-stroke behavior. Chapter 12 explores presynaptic dysfunction as a key aspect of Parkinson’s disease, offering insights into how it contributes to the disorder’s pathophysiology. Chapter 13 highlights the involvement of mitochondrial dysfunction in various neurological disorders, highlighting its significance in their development and progression. Chapter 14 investigates the intricate molecular and cellular mechanisms through which pathogens invade the central nervous system, focusing on the specific case of meningitis. Chapter 15 addresses the topic of muscular dystrophy with a specific focus on mutations occurring in the dystrophin gene.
Preface
ix
Chapter 16 investigates the application of gene editing tools for the treatment and management of neurodegenerative diseases, providing insights into their potential therapeutic benefits. Chapter 17 provides a comprehensive overview of lumbar disc disease, offering insights into its causes, symptoms, and management. Lucknow, India Tampa, FL, USA Sharjah, United Arab Emirates
Andleeb Khan Mashoque Ahmad Rather Ghulam Md Ashraf
Acknowledgments
Kindness is much more than deeds. It is an attitude, an expression, a look, or even a gentle touch. It is anything that lifts another person. In this little space, we try to acknowledge the support and inspiration of all the people who have been a part of our lives and have contributed knowingly or unknowingly in successful completion of this book. The Editors of the book wholeheartedly acknowledge all the contributors of the book without whom this book would have not been a success. The Editors also acknowledge the Publishers and the team associated for their constant support and timely guidance. We would like to give our special thanks to Mr. Bhavik Sawhney and Ms. Nandhini Viswanathan for their constant guidance and inspiration which regularly thrust us to the core to complete this book. The Editors also thank their family members and friends for their constant support and motivation. Additionally, the editors are sincerely appreciative of all who have directly or indirectly offered important inputs to this book.
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Contents
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Neuropathology of Neurological Disorders �������������������������������������������� 1 Mashoque Ahmad Rather, Andleeb Khan, Hayate Javed, Sadaf Jahan, Rizwana Tabassum, and Rubia Begum
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Head Trauma: Etiology, Pathophysiology, Clinical Manifestation, and Biomarkers������������������������������������������������������������������������������������������ 35 Liam Goldman, Mario P. Espinosa, Manish Kumar, Luca H. Debs, Fernando L. Vale, and Kumar Vaibhav
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Current Understanding of DNA Methylation in the Pathogenesis of Neuropathic Pain���������������������������������������������������������������������������������������� 59 Hayate Javed, Aishwarya Mary Johnson, and Andleeb Khan
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Decoding Dystrophin Gene Mutations: Unraveling the Mysteries of Muscular Dystrophy���������������������������������������������������������������������������������� 75 Zeenat Mirza and Sajjad Karim
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Etiology of Ataxia: A Mechanistic Insight of Autoimmune, Toxicity, and Genetic Approach ������������������������������������������������������������������������������ 91 Rizwana Tabassum, Anju Katyal, Chandrawati Kumari, and Mashoque Ahmad Rather
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miRNA Dysregulation in Schizophrenia�������������������������������������������������� 117 Mohammed Kaleem, Ritesh Fule, Mahmoud Alhosin, Kishor Danao, Sachin M. Mendhi, Ujwala Nandkumar Mahajan, Wasim Ahmad, Nitin G. Dumore, Waseem Mohammed Abdul, and Mangesh D. Godbole
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Muscular Dystrophy: Underlying Cellular and Molecular Mechanisms and Various Nanotherapeutic Approaches for Muscular Dystrophy���������������������������������������������������������������������������������� 145 Durafshan Sakeena Syed, Mohamad Sultan Khan, Urba Afnan, Mohd Jamaal Dar, and Tariq Maqbool
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Axonal Degeneration, Impaired Axonal Transport, and Synaptic Dysfunction in Motor Neuron Disorder�������������������������������������������������� 199 Sabra Parveen, Farheen Showkat, Neetu Badesra, Mohmmad Saleem Dar, Tariq Maqbool, and Mohd Jamal Dar xiii
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Contents
Alterations in Receptor Genes in Huntington’s Disease������������������������ 231 Tarun Kumar Suvvari, Ayush Anand, Shivangi Srivastava, and Mainak Bardhan
10 Genetic Modulators in Amyotrophic Lateral Sclerosis�������������������������� 255 Babita, Sonal Gaur, Anil Kumar Mavi, and Harsh Vardhan 11 Modulators and Poststroke Behavioral Changes������������������������������������ 273 Rahul Saxena, Babita, Suyash Saxena, and Sudipta Kundu 12 Presynaptic Dysfunction in Parkinson’s Disease������������������������������������ 285 Koyel Kar 13 Mitochondrial Dysfunction and Its Role in Neurological Disorders���������������������������������������������������������������������������������������������������� 299 Gulzar Ahmed Rather, Vishal Mathur, Muzafar Riyaz, Raman Yadav, Anima Nanda, Arif Jamal Siddiqui, Mashoque Ahmad Rather, Andleeb Khan, and Sadaf Jahan 14 Molecular and Cellular Mechanism of Pathogen Invasion into the Central Nervous System: Meningitis ������������������������������������������������ 317 Priyanka Singh, Komal Gupta, Manu Sharma, and Shobhit Kumar 15 Muscular Dystrophy: Mutations in the Dystrophin Gene��������������������� 341 Aishwarya Agarwal, Kunal Verma, Shivani Tyagi, Khushi Gupta, Satish Kumar Gupta, Shrestha Sharma, and Shobhit Kumar 16 Gene Editing Tool for Neurodegenerative Diseases�������������������������������� 359 Mohd Yasir Khan, Hamda Khan, Farah Maarfi, Afreen Khanam, Ziaul Hasan, and Arbab Husain 17 Lumbar Disc Disease: An Overview�������������������������������������������������������� 391 Shivani Patel, Santhana Kumar, Arun Soni, Sanjeev Acharya, and Niyati Acharya
Editors and Contributors
About the Editors Andleeb Khan is an Associate Professor in Integral University, Lucknow, India. She has completed her doctorate from Jamia Hamdard, New Delhi, India in Toxicology with specialization in natural and active constituents from plants for prevention of Alzheimer’s Disease. She has joined as Faculty at Jazan University, Saudi Arabia. She has a teaching and research experience of more than 10 years in neurodegenerative disorders and their prevention with medicinal plants, their active principles and nanoformulations. Her accomplishment at academics in Master course is outstanding and was able to get the gold medal, the highest accomplishment for the topper of this course. She has published more than 100 of research publication in national and international journals and contributed many book chapters with international publishers. Dr. Khan is on the editorial board panel and reviewer of various international journals. Dr. Khan is handling many projects of national and international importance. She has received many awards, appreciations, and recognitions for her services to the science. She holds life memberships of various international organizations and is active participant in national and international scientific events. Currently, Dr. Khan is engaged in studying the molecular mechanism of Alzheimer’s disease, Ischemic stroke, Parkinson’s Disease and their prevention by various active principles from natural sources and nanoformulations. Mashoque Ahmad Rather is a highly accomplished Postdoctoral Research Associate in the Department of Molecular Pharmacology and Physiology at the College of Medicine, University of South Florida, United States. His academic journey and research career have been distinguished by a deep commitment to understanding the critical neuroscientific aspects, particularly in the context of Alzheimer’s Disease. Dr. Rather’s educational background includes a doctorate in Biotechnology, with a specialization in neuroscience, which he earned from Annamalai University in Tamil Nadu, India. His rigorous training and expertise in the field of neuroscience have served as a solid foundation for his subsequent research endeavors.With over 8 years of dedicated research experience, Dr. Rather has made significant contributions to the scientific community. He has an impressive track record of authoring numerous research papers published in reputable international journals. Additionally, his expertise extends to the creation of insightful book chapters that have further xv
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enriched the scientific literature. Dr. Rather is a reviewer of various international journals. At present, Dr. Rather is deeply immersed in an exciting and vital area of research. He is actively engaged in investigating the molecular mechanisms underlying Tau pathology and cerebral vascular dysfunction in Alzheimer’s Disease. His work in this field holds great promise for shedding light on the complex biological processes involved in Alzheimer’s Disease, potentially leading to valuable insights for the development of future therapeutic interventions. Ghulam Md Ashraf is working as an Associate Professor in the Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates. He has a PhD degree in Biochemistry with over 12 years of teaching and research experience in various disciplines of biological and medical sciences. Dr. Ashraf has taught various subjects like Biochemistry, Biology, Clinical Biochemistry, Cell Biology, Genetics, Immunology, Intellectual Property Rights, Introduction to Research, Molecular Biology, Neurology, Recombinant DNA, and Research Methods Technology at graduate and post-graduate levels.His primary fields of research are biochemistry and neurology, currently focusing on understanding the molecular and behavioral mechanism of effects of anti-diabetic drugs in psychotic and dementia conditions. Dr. Ashraf’s lab is currently investigating the effect of anti-diabetic drugs in the possible attenuation/reversal of anti-psychotic drugs induced weight gain in psychotic conditions. He is also investigating molecular and behavioral mechanisms of novel therapeutic combinations in multiple sclerosis and Alzheimer’s disease. Dr. Ashraf has published 398 research articles (citations: 10289, H-index: 53, i10 index: 210) and have been involved in 25 research grants [4 ongoing (1 PI, 3 CoI) and 21 completed (17 PI, 4 CoI)]. He has supervised 3 PhD, 2 masters, and 7 bachelor students in their research projects. Dr. Ashraf has served as examiner of 9 PhD and master theses and have assessed 4 research grant applications.Dr. Ashraf is also involved extensively in editorial roles in renowned scientific journals. He has to his credit 397 Publons verified editor records, and 629 Publons verified reviewer records. Dr. Ashraf has been involved as guest editor of 21 special issues in reputed international journals. He is professionally associated with the Royal Society of Medicine (Fellow), Royal Society of Biology (Member), American Society for Biochemistry and Molecular Biology (Member), and Canadian Association of Neuroscience (Member).For his scientific contributions, Dr. Ashraf was approved as a subject of biographical record in Marquis Who’s Who in the World (2020). Dr. Ashraf has been recognized as Expertscape World Expert in Alzheimer’s disease and Neurodegenerative Disorders. Most recently, he has been listed in Top 2% Scientists Worldwide since 2021. Orcid: https://orcid.org/0000-0002-9820-2078 Scopus: https://www.scopus.com/authid/detail.uri?authorId=16444016700
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Web of science: https://www.webofscience.com/wos/author/record/H-9485-2012 Google scholar: http://scholar.google.com/citations?user=-fOCOTQAAAAJ&hl=en
Contributors Waseem Mohammed Abdul Mumtaz Degree and PG College (Osmania University), Hyderabad, India Niyati Acharya Department of Pharmacognosy, Faculty of Pharmacy, Nirma University, Ahmedabad, India Sanjeev Acharya Department of Pharmacology, SSR College of Pharmacy, Silvassa, Union Territory of Dadra and Nagar Haveli & Daman Diu, India Urba Afnan Laboratory of Nanotherapeutics and Regenerative Medicine, Department of Nanotechnology, University of Kashmir, Srinagar, India Indian Institute of Technology (IIT) Bombay, Mumbai, India Aishwarya Agarwal Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, Uttar Pradesh, India Wasim Ahmad Department of Kuliyate Tib, National Institute of Unani Medicine, Bengaluru, India Mahmoud Alhosin Department of Biochemistry, King Abdul-Aziz University, Jeddah, Kingdom of Saudi Arabia Ayush Anand BP Koirala Institute of Health Sciences, Dharan, Nepal Babita Department of Pharmacology, Sharda School of allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India CEGMR, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia Neetu Badesra Laboratory of Cell and Molecular Biology, Department of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, India Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, India Mainak Bardhan ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India Department of Neuro Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA Rubia Begum Department of Biosciences, Faculty of Science, Integral University, Lucknow, India Kishor Danao Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra, India
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Mohd Jamaal Dar Laboratory of Cell and Molecular Biology, Department of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, India Mohmmad Saleem Dar Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, India Luca H. Debs Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA Nitin G. Dumore Department of Pharmacology, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra, India Mario P. Espinosa Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA Ritesh Fule Department of Pharmaceutics, Dadasaheb Balpande College of Pharmacy, Nagpur, India Sonal Gaur Department of Bioscience and Biotechnology, Banasthali Vidyapith, Jaipur, Rajasthan, India Mangesh D. Godbole Department of Pharmaceutical Quality Assurance, Dadasaheb Balpande College of Pharmacy, Nagpur, India Liam Goldman Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA Khushi Gupta Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, Uttar Pradesh, India Komal Gupta Department of Pharmaceutics, Galgotias College of Pharmacy, Greater Noida, India Satish Kumar Gupta School of Pharmaceutical and Population Health Informatics, DIT University, Dehradun, Uttarakhand, India Ziaul Hasan Department of Biosciences, Jamia Millia Islamia, New Delhi, India Arbab Husain Department of Biotechnology and Life Sciences, Institute of Biomedical Education and Research, Mangalayatan University, Aligarh, India Mir Ashiq Hussain Department of Chemistry, Pondicherry University, Puducherry, India Sadaf Jahan Department of Medical Laboratory Science, College of Applied Medical Sciences, Al Majmaah, Kingdom of Saudi Arabia Hayate Javed Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates Aishwarya Mary Johnson Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Mohammed Kaleem Department of Biochemistry, King Abdul-Aziz University, Jeddah, Kingdom of Saudi Arabia Department of Pharmacology, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra, India Sajjad Karim Department of Medical Laboratory Sciences, FAMS, KAU, Jeddah, Kingdom of Saudi Arabia Koyel Kar Department of Pharmaceutical Chemistry, BCDA College of Pharmacy and Technology, North 24 Parganas, West Bengal, India Anju Katyal Dr. B.R. Ambedkar Center for Biomedical Research (ACBR), University of Delhi (North Campus), New Delhi, Delhi, India Afreen Khanam Department of Biotechnology and Life Sciences, Institute of Biomedical Education and Research, Mangalayatan University, Aligarh, India Andleeb Khan Department of Biosciences, Faculty of Science, Integral University, Lucknow, India Hamda Khan Department of Biochemistry, Jawahar Lal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India Mohamad Sultan Khan Neurobiology and Molecular Chronobiology Laboratory, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India Mohd Yasir Khan Department of Biotechnology, School of Applied and Life Sciences (SALS), Uttaranchal University, Dehradun, Uttarakhand, India Chandrawati Kumari ICMR-Centre of Excellence for Fluorosis Research, Fluorosis Research and Rural Development Foundation, New Delhi, Delhi, India Manish Kumar Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA Santhana Kumar Department of Pharmacology, SSR College of Pharmacy, Silvassa, Union Territory of Dadra and Nagar Haveli & Daman Diu, India Shobhit Kumar Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, India Sudipta Kundu Department of Human Physiology, Kalka Dental College, Meerut, Uttar Pradesh, India Farah Maarfi Department of Biotechnology, School of Applied and Life Sciences (SALS), Uttaranchal University, Dehradun, Uttarakhand, India Ujwala Nandkumar Mahajan Department of Pharmaceutical Quality Assurance, Dadasaheb Balpande College of Pharmacy, Nagpur, India
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Tariq Maqbool Laboratory of Nanotherapeutics and Regenerative Medicine, Department of Nanotechnology, University of Kashmir, Srinagar, India Vishal Mathur Department of Pharmaceutical Chemistry, School of Pharmaceutical Chemistry, Jamia Hamdard, New Delhi, India Anil Kumar Mavi Department of Pulmonary Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, Delhi, India Sachin M. Mendhi Department of Pharmacology, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra, India Zeenat Mirza King Fahd Medical Research Center, KAU, Jeddah, Kingdom of Saudi Arabia Department of Medical Laboratory Sciences, FAMS, KAU, Jeddah, Kingdom of Saudi Arabia Sabra Parveen Laboratory of Cell and Molecular Biology, Department of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, India Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, India Shivani Patel Department of Pharmacology, SSR College of Pharmacy, Silvassa, Union Territory of Dadra and Nagar Haveli & Daman Diu, India Gulzar Ahmed Rather Department of Biomedical Engineering, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India Mashoque Ahmad Rather Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA Muzafar Riyaz Xavier Research Foundation, St. Xavier’s College, Palayamkottai, Tamil Nadu, India Rahul Saxena Department of Biochemistry, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India Suyash Saxena Department of Biochemistry, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India Manu Sharma Department of Pharmacy, Banasthali Vidyapith, Jaipur, Rajasthan, India Shrestha Sharma Amity Institute of Pharmacy, Amity University, Haryana, Gurugram, Haryana, India Farheen Showkat Laboratory of Cell and Molecular Biology, Department of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, India Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, India Arif Jamal Siddiqui Department of Biology, College of Science, University of Hail, Hail, Kingdom of Saudi Arabia
Editors and Contributors
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Priyanka Singh Department of Pharmaceutics, Galgotias College of Pharmacy, Greater Noida, India Department of Pharmacy, Banasthali Vidyapith, Jaipur, Rajasthan, India Arun Soni Department of Pharmacology, SSR College of Pharmacy, Silvassa, Union Territory of Dadra and Nagar Haveli & Daman Diu, India Shivangi Srivastava T.S. Misra Medical College and Hospital, Lucknow, India Tarun Kumar Suvvari Rangaraya Medical College, Kakinada, India Squad Medicine and Research (SMR), Visakhapatnam, Andhra Pradesh, India Durafshan Sakeena Syed Department of Molecular Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA Rizwana Tabassum Dr. B R Ambedkar Center for Biomedical Research (ACBR), University of Delhi (North Campus), New Delhi, Delhi, India Shivani Tyagi Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, Uttar Pradesh, India Kumar Vaibhav Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA Department of Oral Biology and Diagnostic Sciences, Center for Excellence in Research, Scholarship and Innovation, Dental College of Georgia, Augusta University, Augusta, GA, USA Transdisciplinary Research Initiative in Inflammaging and Brain Aging (TRIBA), Augusta University, Augusta, GA, USA Fernando L. Vale Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA Harsh Vardhan Department of Pulmonary Medicine, All India Institute of Medical Science, Jodhpur, India Kunal Verma Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, Uttar Pradesh, India Raman Yadav Department of Pharmacology, Sri Ramachandra Medical College and Research Institute, SRIHR, Chennai, Tamil Nadu, India
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Neuropathology of Neurological Disorders Mashoque Ahmad Rather, Andleeb Khan, Hayate Javed, Sadaf Jahan, Rizwana Tabassum, and Rubia Begum
Abstract
Neuropathology delineates the examination of cells and tissues, to assimilate the structure and function of the neurological system as well as the diagnosis and pathology of diseases that impact the nervous system. It studies the effects of disease on the nervous system and can be used to diagnose and categorize particular neurological conditions. This comprises studies of the muscles, nerves, and ganglia (the peripheral nervous system), and the brain and spinal cord (the central nervous system). A wide array of techniques such as immunohistochemistry, molecular biology, and light and electron microscopy are being used to observe neuropathological alterations in various neurological disorders. Neuropathology highlights the structural and functional observations of neurological diseases ranging from cellular to micro-anatomical constructs to identify the biomarkers that are responsible for the progression of the diseases. Several imaging technologies are also used which include CT scans and MRI to deeply M. A. Rather (*) Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA A. Khan (*) · R. Begum Department of Biosciences, Faculty of Science, Integral University, Lucknow, India H. Javed Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates S. Jahan Department of Medical Laboratory Science, College of Applied Medical Sciences, Al Majmaah, Saudi Arabia R. Tabassum Dr. B R Ambedkar Center for Biomedical Research (ACBR), University of Delhi, Delhi, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_1
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examine the modifications in neurological disorders. The examination of several neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, rests severely on neuropathology. In this chapter, we will discuss about the neuropathology of several neurological disorders. Keywords
Neuropathology · Amyloid-β · Tau · Lewy bodies · HTT gene · MS · CVDs
1.1 Introduction Neurological disorders involve a wide range of conditions that affect the structure and function of the nervous system, resulting in a variety of symptoms and limitations. These disorders can be caused by several factors, such as genetic mutations, infections, environmental influences, autoimmune responses, and degenerative processes. To understand their underlying processes and symptoms, a thorough examination of their neuropathology is crucial venture. Neuropathology looks into the structural and molecular changes that occur in the nervous system as a result of disease or injury. It focuses on the analysis of tissue samples taken from the brain, spinal cord, and nerves through autopsy, surgery, or biopsy. Neuropathologists can identify the precise changes and anomalies linked to various neurological disorders by microscopic examination of the tissue samples. Finding the pathological markers or lesions that characterize particular disorders is one of the core parts of neuropathology. These distinguishing characteristics might manifest in several ways, such as aberrant protein aggregation, neuronal loss, inflammation, demyelination, and vascular abnormalities. These distinguishing characteristics aid in the establishment of diagnostic standards and therapeutic approaches and offer vital insights into disease progression. To understand the genetic underpinnings of neurological disorders, neuropathology is equally crucial. The identification of several disease-causing genes and the detection of genetic alterations linked to a variety of disorders have been made possible by advancements in molecular techniques. Researchers can identify particular genetic defects that contribute to the onset and progression of neurological diseases by analyzing DNA and RNA extracted from patient samples. Neuropathology also helps us understand how diseases develop and how their symptoms are related to one another clinically. Researchers can clarify the temporal and spatial patterns of pathological alterations by studying the brain and spinal cord tissues at various stages of the disease. This information aids in the creation of tailored treatment approaches, the establishment of disease staging systems, and prognosis prediction. The intricate interactions between distinct cell types in the nervous system are further illuminated by the neuropathology of neurological disorders. In response to disease, several cell groups, such as immune cells, glial cells, and neurons, can experience pathological changes. Understanding the mechanisms driving neuronal malfunction, inflammation, neurodegeneration, and neurorepair is made possible by the study of these biological alterations.
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Thus, unraveling the underlying causes of neurological disorders, identifying diagnostic indicators, and creating efficient treatments depend on a thorough understanding of the neuropathology of these conditions. The discipline of neuropathology continues to offer essential insights into the intricate structure of neurological disorders by implementing advanced technical breakthroughs, opening the way for improved diagnosis, treatment, and management of these conditions. The most common neurological disorders include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS), which are usually progressive and may worsen over time. The symptoms of these diseases vary depending on the type, and they can range from mild to severe. Therefore, in this chapter, we will discuss about the neuropathology of several neurological disorders.
1.2 Degenerative Disorders Degenerative diseases are a group of medical conditions that gradually deteriorate the body’s cells and tissues. These diseases are typically chronic and can deteriorate over time. The most prevalent degenerative disorders are AD, PD, and HD. The symptoms of these diseases vary depending on the type, and they can range from mild to severe. Thus, the risk factors, pathological alterations, clinical manifestations, and progression of the diseases have been given in Table 1.1.
1.2.1 Alzheimer’s Disease The most typical cause of dementia is AD, a progressive, neurodegenerative ailment depicted by psychological and behavioral symptoms as well as a slow deterioration of cognitive function. The underlying pathology of AD consists of two irregular protein fragments called Aβ lesions and neurofibrillary tangles (NFTs) in the brain. Amyloid plaques consist of the β-amyloid (Aβ) peptide, which is generated by the cleavage of amyloid precursor protein (APP). Aβ peptides are produced in a variety of lengths, with Aβ42 being the most common and most toxic form. These plaques accumulate in several brain sections, including the neocortex, hippocampus, and amygdala (Liu et al. 2019). The NFTs are comprised of hyperphosphorylated tau, which accumulates in the neurons of the brain (Ahmad et al. 2019; Arafah et al. 2023). Tau proteins are typically found in the axons of neurons, where they help to stabilize microtubules and maintain the proper shape of the cell. In AD, tau proteins become abnormally phosphorylated and aggregate together to form NFTs. These tangles are most commonly found in the hippocampus, amygdala, thalamus, and basal ganglia. Besides NFTs and Aβ lesions, AD is also characterized by oxidative stress, neuroinflammation, and synaptic dysfunction (Rehman et al. 2023). Astrocytes, activated microglia, and pro-inflammatory cytokines are all indicators of neuroinflammation in the brain (Rather et al. 2021). Oxidative stress is brought on by an excess of reactive oxygen species (ROS), which can harm cellular
Environmental factors, past traumatic brain injury, exposure to toxic substances, and drugs and medication
Genetic mutation, age, sex, and familial history
PD
HD
Disorders Risk factors AD Genetic predisposition, environmental factors, infections, trauma, toxic substances
Clinical presentation Memory loss, language difficulties, vision loss, mood swings, and personality changes Body tremor, muscle rigidity, mood swings, sleep disorder, fatigue, speech and cognitive problems Involuntary movements, cognitive decline, psychiatric disturbances, and various motor and behavioral alterations
Functional alterations Impaired neuronal signaling, altered neurotransmitter release, disrupted neuronal circuits, sensory disturbances, and cognitive decline Motor abnormalities, loss of functional mobility, and stooped posture
Disrupted signal transmission, basal ganglia impairment, imbalance of neurotransmitters, cognitive decline, dystonia, bradykinesia, and anxiety
Pathological alterations Abnormal protein accumulation of Aβ and Tau, neuroinflammation, oxidative stress, synaptic loss, and neuronal death
Dopaminergic neuronal damage in the basal ganglia, particularly in the substantia nigra, and atypical Lewy body formation from α-synuclein
Mutation in the HTT gene, production of mutant huntingtin protein, aggregation of abnormal protein, impairment in protein trafficking, calcium homeostasis, and neuronal dysfunction
Clinical evaluation, genetic testing, and medical imaging such as MRI and computed tomography Neuroinflammation, excitotoxicity, neurotransmitter impairment, disruption in cellular transport, mitochondrial dysfunction, synaptic loss, neuronal dysfunction, age, and environmental and lifestyle factors
Dopamine depletion, Lewy body formation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurotransmitter imbalance
Diagnosis Clinical assessment (history, physical examination), neuroimaging, biomarker analysis (CSF, blood tests), and neurophysiological testing Medical history, parkinsonian symptoms, and response to levodopa imaging tests
Disease progression Further accumulation of pathological changes, increased functional impairment, and potential involvement of additional brain regions
Vonsattel et al. (2008), Gu et al. (2005), Spampanato et al. (2008)
Schulz- Schaeffer (2010), Dexter and Jenner (2013), Tufekci et al. (2012)
References Hardy (2009), Salomone et al. (2012), Roth et al. (2005)
Table 1.1 An overview of risk factors, pathological and functional alterations, clinical presentations, and diagnosis in different neurological disorders
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Disorders Risk factors MS Genetic and environmental factors, gender, and age
Pathological alterations Inflammatory demyelination, lesion formation throughout the CNS, reactive gliosis, and gray matter damage
Functional alterations Motor function impairment, damage to sensory pathways, fatigue, cognitive dysfunction, and bladder and bowel dysfunction
Clinical presentation Optic neuritis, fatigue, numbness, depression, and walking difficulties Disease progression Autoimmune response, inflammation, axonal damage, demyelination, neuroplasticity, and neurodegeneration
Diagnosis Medical history, neurological examination, CSF analysis, evoked potentials, and imaging analysis
References Kornek and Lassmann (2003), Lemus et al. (2018), Ghasemi et al. (2017)
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structures and result in cell death. Synaptic dysfunction is due to the loss of synapses in the brain, which is thought to be caused by the accumulation of Aβ plaques and NFTs (Khan et al. 2012a). The Aβ, tau, and inflammatory assumptions are only a few of the assumptions that have been advanced to explain this complex disorder (Kumar and Dogra 2008). Researchers have highlighted the function of Aβ oligomers in synaptic damage, demonstrating that Aβ oligomers are one of several factors to disfigure the neuronal integrity (Anand et al. 2014; Dal Prà et al. 2014). The amyloid cascade hypothesis postulates that the APP is processed abnormally by β- and γ-secretases after being normally cleaved by α-secretase, resulting in an imbalance in the synthesis and clearance of Aβ peptide (Salomone et al. 2012). As a result, Aβ peptides instinctively aggregate into soluble oligomers, then combine to form insoluble fibrils, which are subsequently accumulated as diffuse senile plaques (Hardy 2009). According to research by Kurz and Perneczky (2011), Aβ42 oligomers cause oxidative damage, encourage hyperphosphorylation of Tau protein, and have a negative impact on synapses and mitochondria. Proinflammatory cytokines, such as TNF, IL-1β, and IFN-γ, are generated and released when microglial cells are activated. Consecutively, these cytokines activate further Aβ42 production and distribution by encouraging the adjacent astrocyte- neuron to generate more Aβ42 oligomers (Dal Prà et al. 2014). Aβ oligomers are believed to be the cause of the neuronal degeneration in AD brains, which causes oxidative damage and reduces the ability of the neurons to scavenge free radicals (Roth et al. 2005; Galimberti et al. 2013). The clearance of Aβ oligomers from the brain is primarily mediated by the insulin-degrading enzyme (IDE) and proteases neprilysin-mediated proteolytic degradation, astrocytes, and microglia (Yasojima et al. 2001; Braak and Del Tredici 2011). Increased NO levels have been shown to inhibit IDE’s enzymatic activity, which leads to the build-up of Aβ oligomers in the brain and the onset of AD (Tuppo and Arias 2005). According to earlier research, hyperphosphorylated tau oligomers and Aβ42 oligomers diffuse via exocytosis to astrocyte and oligodendrocyte target cells, which then develop into cells that manufacture Aβ and tau oligomers (Eisele et al. 2010).
1.2.1.1 Amyloid Plaques The amyloid cascade hypothesis was evolved in response to the illustration of Aβ as an essential component of Aβ plaques (Hardy and Selkoe 2002), and genetic affirmation linking the APP protein and its processing by β- and γ-secretases to autosomal dominant AD forms (Goate et al. 1991; Levy-Lahad et al. 1995). Research studies investigated that Aβ deposits diffuse in the brain in a routine style that can be categorized into five distinct phases (Thal et al. 2002). The first phase reveals its early deposition in the neocortex, and, the second, its development is seen in the limbic areas which include amygdala, entorhinal cortex, subiculum, and cingulate gyrus. In the third phase, Aβ accumulates in subcortical areas including the thalamus and basal ganglia, followed by the fourth phase which
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affects the midbrain, pons, and medulla oblongata, and then finally it spreads to the cerebral cortex. There are perceptible amounts of accumulates in the cerebral blood vessels called cerebral amyloid angiopathy (CAA), which is commonly observed in AD patients, in addition to the production of Aβ aggregates in the brain parenchyma (Bergeron et al. 1987; Jellinger et al. 2007). The breakdown of blood artery walls and subsequent risk of cerebral hemorrhages are critical side effects of vascular Aβ deposition (McCarron and Nicoll 1998). Deterioration of this process appears to be a significant contributing element to the onset of sporadic AD (Greenberg et al. 2020). The severity of arterial wall integrity damage and the location of CAA throughout the brain have both been rated using several neuropathological staging approaches to quantify CAA (Vonsattel et al. 1991; Thal et al. 2010). Whichever of these conditions is employed, it is evident that more severe pathology is connected to more intense outcomes, such as micro- or macro-hemorrhage or infarcts (Thal et al. 2010). The biomarkers enable the monitoring of the appearance of Aβ accumulates in AD subjects. Researchers suggested that imaging using Aβ-specific positron emission tomography (PET) ligands could provide a generalized picture of Aβ pathology’s regional distribution (Hampel et al. 2021). A reduction of Aβ1–42 or of the ratio of Aβ1–42/Aβ1–40 is a good predictor of Aβ pathology in the brain. To validate that the performance of biomarkers is as accurate as predicted in individuals treated with Aβ altering treatments, comprehensive autopsy studies are still required.
1.2.1.2 Tau Tau, a protein associated with microtubules, accumulates to form NFTs, the second main pathogenic finding in AD. To find a stereotypical pattern of dissemination of these aggregates, Braak and colleagues used whole hemisphere 100-m-thick sections of 83 brains using silver-staining techniques in a seminal work (Braak and Braak 1991). The hippocampal formation’s trans-entorhinal area (stage I) is where the first NFT were discovered. From then, the number of aggregates increases and spreads to the hippocampal pyramidal cell layer’s subiculum (stage II). “Transentorhinal stages” refers to this early manifestation of NFT pathology (Braak and Braak 1991). NFT begins to affect the hippocampal pyramidal cell layer and entorhinal cortex as the disease progresses, especially sector CA1 (stage III). Sectors CA1–CA4 of the hippocampus pyramidal cell layer and the neighboring inferior temporal cortex are among the regions where the modifications are most pronounced. The superior temporal cortex and frontal cortex are two further neocortical regions where NFT disease has spread (stage IV). Since the hippocampus formation is most severely impacted, these transitional stages are frequently denoted as “limbic stages.” The abnormalities in the hippocampus formation worsen as the disease progresses, but they also impact other parts of the neocortex, such as secondary association areas and finally primary cortical areas. As a result, these advanced illness stages are referred to as “isocortical stages” (Braak and Braak 1991). A segment of the occipital cortex is routinely studied to determine the stages of this progression; stage V is defined by the illness in the
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peristriate area, and stage VI is defined by intraneuronal aggregates in the striate area. While stages I and II are frequently found in clinically asymptomatic subjects, Braak stages V and VI have the best correlation with clinically recognized dementia (Braak and Braak 1991). The development of NFT appears to be caused by tau redistribution from the axonal section to the somatodendritic section and aberrant tau phosphorylation, and studies using antibodies that are specific for phosphorylated tau demonstrated earlier phases of tau aggregation in neurons, presumed pre-tangles (Braak et al. 2011). Additional systematic research was conducted as a result, and some of these purported precursor lesions were observed in the brain’s stem’s neuronal populations, most notably the locus coeruleus. This broadened our understanding of tau pathogenesis in humans with regard to the anatomical distribution and age range of afflicted individuals (Stratmann et al. 2016; Ehrenberg et al. 2017). The hypothesis that tau appears to migrate across physically related places has inspired major research endeavors to uncover a “prion-like” tau spreading mechanism between connected neuronal populations in animal models and possibly even in human AD patients (Dujardin and Hyman 2019). Although the precise methods by which tau may cross synapses to neighboring neurons are yet unknown, understanding this process may be essential to the creation of disease-modifying treatments. The discovery of initial lesions in the locus coeruleus has also prompted investigations into the origins of pathogenic protein aggregation in enteric neurons and putative linkages to peripheral organs (the “gut-brain axis”) (Kowalski and Mulak 2019) (Fig. 1.1).
1.2.2 Parkinson’s Disease PD is a progressive neurodegenerative disease represented by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain. The primary cause of this death is unknown, although it is presumed to be related to genetic, environmental, and/or lifestyle factors. Tremor, stiffness, bradykinesia, and postural instability are just a few of the symptoms that develop as the illness worsens (Reich and Savitt 2019). The pathology of PD involves the degeneration of dopaminergic neurons in the substantia nigra pars compact (SNpc), as well as the presence of intraneuronal inclusions called Lewy bodies (LBs) (Raza et al. 2019; Aryal et al. 2020). These LBs are made up of aggregates of proteins, including α-synuclein, ubiquitin, and neurofilament proteins. The presence of LBs is considered to be the cause of the dopaminergic cell death, as these aggregates are toxic to the neurons (Khan et al. 2012b). Besides the loss of dopaminergic neurons, PD is also associated with other neuropathological changes, including gliosis, inflammation, and the existence of aberrant mitochondria. Gliosis is the replacement of lost neurons by astrocytes and microglia, which can worsen brain inflammation and injury. Pro-inflammatory cytokines are released during inflammation, which can cause neuronal damage and the formation of LBs. Abnormal mitochondria can also contribute to neuronal death, as they are unable to produce sufficient energy for the cell to function properly (Khan et al. 2012b). Overall, PD is a complex disorder that involves an array of different
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Fig. 1.1 Pathology of AD. The formation of amyloid plaques is associated with the production of Aβ peptides. Alterations in the APP lead to an increased cleavage by β-secretase, contributing to the production of these peptides. Additionally, PSEN1/PSEN2 leads to augmented activity of γ-secretase, further promoting the Aβ peptide production and the development of Aβ lesions. These Aβ lesions subsequently induce hyperphosphorylation of the Tau protein, oxidative stress, excitotoxicity, and disruptions in synaptic function. Therefore, these peptide aggregates stimulate oxidative stress and facilitate inflammatory processes within neurons. This inflammatory response, in turn, amplifies the expression of APP, leading to increased production of Aβ peptides. Hence, this process ultimately culminates in neuronal damage and AD progression
pathological changes. The primary cause of death is the deterioration of dopaminergic neurons in the substantia nigra, along with the occurrence of LBs. The neuropathology of PD also involves changes in other brain areas, such as the basal forebrain, hippocampus, and amygdala. In the basal forebrain, neurons that produce the neurotransmitter acetylcholine (ACh) begin to die, resulting in a decrease in the amount of ACh available to the brain (Alexander 2004). This can lead to memory and behavioral deficits, as well as disturbances in motor control. The hippocampus is also affected in PD, as it is a major target of the dopaminergic neurons. Neuronal degeneration in the hippocampus can lead to memory impairments and difficulty with learning new information (Llewelyn et al. 2022). The amygdala brain region is involved in the processing of emotions and motivation. Neuronal disintegration in this region has been connected to changes in mood and behavior, as well as an overall decrease in motivation (Khan et al. 2010). Finally, PD is also associated with changes in the cerebellum, which controls balance and coordination. Neuronal loss in this region can lead to an increased risk of falls, as well as difficulty with fine motor control (Wu and Hallett 2013). Overall, the
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neuropathology of PD involves a variety of different changes in the brain, all of which can contribute to the progression of the illness. The primary cause of death is still unknown, but various environmental, genetic, and lifestyle factors are believed to play a role. The LBs and dystrophic neurites within nerve pathways, as well as within the synaptic compartment, are hallmarks of the histopathology of PD. These pathological characteristics are particularly concentrated within the presynaptic terminals across the CNS (Muntane et al. 2008; Schulz-Schaeffer 2010). Numerous subcortical nuclei, particularly the substantia nigra compacta (SNc), locus coeruleus, and dorsal motor nucleus of vagus, as well as many other neuronal systems, are linked to variable neuron loss. The A-9 group of SNc is severely affected by the reduction of melanized and dopaminergic neurons that express tyrosine hydroxylase (TH), an essential substance for dopamine production. This leads to striatal denervation and dopamine decline of 44–98%, which are symptoms of nigrostriatal degeneration (Rajput et al. 2008). As dopamine degenerates, initial disease stages witness a rise in striatal dopaminergic neurons, possibly due to phenotypic shifts rather than neurogenesis (Porritt et al. 2006; Tandé et al. 2006). While MRI studies revealed early striatal volume deviations, similar alterations in the olfactory bulb might imitate a compensatory mechanism (Mundinano et al. 2011) that may be more effective in younger PD subjects (de la Fuente-Fernandez et al. 2011). In early-onset PD, nigrostriatal dopaminergic neuron loss is greater than in late- onset PD (Shih et al. 2007). The dopamine impairment was discovered by longitudinal PET investigations approximately a decade before the onset of the disease in older PD patients. This impairment might even exist for up to 25 years prior to symptoms in younger subjects. Thus, the period before clinical symptoms varies depending on the age of onset. Prior to the inception of motor symptoms, the dopaminergic system can sustain more damage in younger PD subjects. The final-stage PD patients displayed a dramatic loss of SN neurons along with substantial cell atrophy (Rudow et al. 2008). Recent SPECT investigations, however, showed that even after many years of sickness, the dopaminergic system is not completely degenerated, with the loss being more pronounced in the putamen than in the caudate nucleus (Djaldetti et al. 2011). Before the degeneration of SN cells, various indicators of functional neuronal damage are already affected. This includes the loss of neurofilament proteins, mRNA, immunoreactivity of neuronal TH and DAT, as well as cyclooxygenase (COX) activity (Kingsbury et al. 1999). The loss of neurons is accompanied by an astroglial response, neuronophagia, and extracellular neuromelanin release that is taken up by macrophages (McGeer and McGeer 2008). In the afflicted nigrostriatal system, there is evidence of microglial activation and associated dopaminergic terminal loss point to the possibility that neuroinflammatory reactions play a role in the ongoing degenerative process (Pradhan and Andreasson 2013; Tufekci et al. 2012). In PD, α-Syn plays a significant part in the development and maintenance of inflammation (Alvarez-Erviti et al. 2011). However, this role appears to shift from being beneficial in the disease
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Fig. 1.2 Pathology of PD. The α-synuclein monomers undergo a process of aggregation, transitioning from individual molecules to α-synuclein oligomers. These oligomers then further assemble into fibrils. This sequence of events ultimately contributes to the development of Lewy body (LB) pathology, a hallmark of PD. The deposition of LBs within motor neurons precipitates neuronal dysfunction. Mutations in genetic factors are implicated in the disease’s onset. Additionally, neuroinflammation and excitotoxicity in neurons lead to increased oxidative stress. This, in turn, triggers dysfunction in mitochondria; as a consequence, the mitochondrial membrane potential is disrupted. Ultimately, these cellular disturbances culminate in apoptotic processes, resulting in the degeneration of neurons
stages to become harmful as the disease progresses (Hirsch and Hunot 2009) (Fig. 1.2).
1.2.2.1 Susceptibility of Neurons The intricate web of neurodegenerative marks seen in PD demonstrate a specific susceptibility of midbrain neurons adorned with the enigmatic neuromelanin. These prized neurons reside within the bustling realm of the ventral tier of the SNc, which are rich in dopamine transporter but their energy machinery, the glycolytic enzymes, remains in meager supply. Calbindin, a neuroprotective steward and alert guard against the assault of calcium ions, is curiously lacking from these cells. All of them are projection neurons with unmyelinated or insufficiently myelinated long, thin axons. Increased iron content may be connected to the selective sensitivity of A-9 nigral neurons, rendering them more susceptible to oxidative stress (Zhou et al. 2010; Lv et al. 2011; Sian-Hulsmann et al. 2011). SN neurons with advanced degeneration showed a considerable drop in intracellular pigment, while those with normal morphology display a rise in pigment density linked to greater levels of α-syn. This emphasizes the early neuromelanin alteration’s selectivity for A-9 neurons and the absence of such changes in other
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melanin-containing neurons in the early PD in the A-10 areas (Halliday et al. 2005). Iron enhances α-syn aggregation and controls its expression at the translational stage (Febbraro et al. 2012; Levin et al. 2011). However, the upregulated levels of iron result in the overexpression of α-syn, which causes their selective loss (Fasano et al. 2006; Guerrero et al. 2013). Under oxidative conditions, increased α-syn concentrations near pigment-associated lipids may set off a chain of events that result in intracellular α-syn aggregates and the dispersal of protective pigments, which accelerates cell death (Lv et al. 2011; Halliday et al. 2005; Ruiperez et al. 2010). PD-affected SNc neurons exhibit diminished brain-derived neurotrophic factor (BDNF) expression. The immunohistochemistry revealed almost 20% depletion of glial cell line-derived neurotrophic factor (GDNF) and loss of BDNF within both neuron bodies and their surrounding neuropil as revealed by Chauhan and colleagues in 2001, but enhanced the figures of BDNF and neurotrophin-3 immunoreactive microglia swarming around the beleaguered neurons (Knott et al. 2002), whereas biochemistry reveals no depletion of GDNF in the nigrostriatal regions of PD subjects (Mogi et al. 2001). The mitochondrial impairment emerges as a pivotal player in the depletion of neurons. A distinctive surge in mitochondrial DNA deletions within the SN and other cerebral regions of PD-afflicted brains, relative to age-matched controls, underscores that the impairment of mitochondria is not confined to the SN alone (Gu et al. 2002). This highlights that mitochondrial dysfunction extends beyond the confines of the SN, suggesting that various brainstem clusters are impacted, although dopaminergic SN neurons showcase a more pronounced dependence on mitochondrial bioenergetics and oxidative phosphorylation. Early in the passage of PD, there is a decline in brain mitochondrial metabolism, but it is uncertain whether this is a prime or subsequent event (Winslow and Rubinsztein 2011).
1.2.3 Huntington’s Disease HD is an inherited neurodegenerative ailment that unveils a distressing triad of advancing motor incapacities, cognitive decline, and emotional irregularities (Rather et al. 2023). This affliction is kindled by an undesirable repetition of CAG segments in the huntingtin gene, which leads to an abnormal form of the huntingtin protein (Bogomazova et al. 2019). This protein’s pervasive presence spans the expanse of the brain, orchestrating an intricate symphony of various cellular functions. The pathophysiology of HD is complex and involves both the accumulation of the altered huntingtin protein and the interruption of a multitude of molecular pathways (Snowden 2017). In the brain, the mutant protein accumulates in areas such as the nucleus and striatum, leading to the development of aggregates and the deterioration of neurons. This in turn leads to a series of events including reduced neurotransmission, altered energy metabolism, and inflammation (Bogomazova et al. 2019). The end result is the progressive neuronal damage and the disruption of neural circuits throughout the brain, which results in the characteristic clinical symptoms of HD.
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The gradual disintegration of neurons in the caudate and putamen nuclei of the basal ganglia, in particular, represents the neuropathology of HD. This neuronal loss is connected with a depletion in the figure of normal huntingtin proteins in the brain, as well as an escalation in the number of mutated huntingtin proteins (Van Cauter et al. 2020). These protein aggregates can accumulate in the nucleus and interfere with a wide range of cellular processes, including transcription, synaptic transmission, protein trafficking, and cell survival. This leads to reduced synaptic transmission, impaired energy metabolism, and increased inflammation (Snowden 2017). In addition to neuronal death, gliosis is also seen in the affected brain regions. These alterations lead to a distraction of the dopamine and glutamate neurotransmitter systems, which are involved in cognition, motor control, and behavior (Kandasamy and Aigner 2018). As the disease progresses, these changes can lead to further neuronal death, resulting in further deterioration of motor, cognitive, and behavioral functions. Thus, these alterations can lead to motor deficits, cognitive impairment, and psychiatric disturbances, such as depression and irritability. In addition, there is evidence that the progression of the disease is associated with changes in gene expression, epigenetic modifications, and altered protein expression, which are believed to play a crucial role in the pathogenesis of HD.
1.2.3.1 Basal Ganglia The basal ganglia are an assembly of substantial nuclei that are accountable for controlling mood and movement. They are situated subcortically at the forebrain’s base. The term “basal ganglia” has evolved to encapsulate several key components: the striatum, comprised of the caudate nucleus and putamen, the segment of the globus pallidus, the subthalamic nucleus (STN), and the substantia nigra. Once perceived as the central player in the “extrapyramidal system,” the basal ganglia have undergone a redefining scrutiny (Carpenter et al. 1976; Smith et al. 1998). Among them, the caudate nucleus stands out, stretching its form into a head, a central body, and a dorsal tail area that ventures dorsally over the thalamus and the putamen and divides the striatum into two massive nuclear masses. The internal capsule’s condensed fibers divide the caudate nucleus from the putamen. The globus pallidus, too, unfurls in a dual configuration. The external segment (GPe) and the internal segment (GPi), which are also known as the medial and lateral segments, respectively, make up the globus pallidus. The STN is situated rostro-dorsal to the substantia nigra and medial to the GPi. The SN is divided into two sections: the SNc, tinted with pigmentation in humans and monkeys, clustering dorsally; and the substantia nigra pars reticulata (SNr), taking its place in the midbrain’s ventral recesses. Despite being part of the midbrain, the SN is regarded as belonging to the basal ganglia because of its tight functional and connectivity links with the striatum. 1.2.3.2 Neuropathology of the Basal Ganglia Macroscopic Changes According to several studies (Aylward et al. 1997; Vonsattel and DiFiglia 1998; Vonsattel et al. 2008), the striatum in the postmortem human brain of a subject with
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HD exhibits a dramatic typical bilateral shrinkage. The distribution of this degeneration is often ordered and topographic. The tail and the body of the caudate nucleus exhibit more degeneration than the head in the very initial stages of the degenerative process. According to Vonsattel and DiFiglia (1998), the process of degeneration within the caudate nucleus and the putamen tends to unfold in a specific manner. It follows a distinctive trajectory, commencing from the caudal end of the caudate nucleus and gradually progressing towards its head and body in the caudo-rostral direction. Simultaneously, this degenerative pattern advances both in the dorsal–ventral dimension and along the medio-lateral axis. Macroscopically, the caudate nucleus and putamen’s volume is decreased, which leads to a change in each structure. According to research on 30 HD brains, the caudate nucleus saw a cross-sectional area reduction of 57% whereas the putamen experienced an average loss of 64%. As HD advances, the caudate nucleus undergoes a remarkable transformation. Its distinct convex shape that traditionally outlines the lateral ventricle gradually gives way to a thinner, and eventually more concave appearance. This process contributes to the concurrent expansion of the lateral ventricles, resulting in noticeable changes. This alteration in shape and volume can be attributed to the progressive loss of medium spiny neurons, including their intricate dendritic branching and extensively myelinated axon projections. These cellular losses are chiefly responsible for the continuous reduction in volume. Beyond the neuronal decline, observable gliosis occurs, marked by the response of oligodendrocytes and astrocytes. The foundation of the Vonsattel-grading system, elucidated further below, is built upon evaluating several factors. These include the extent of the caudate nucleus’ macroscopic alteration and the correlated ventricular enlargement, microscopic examination of striatal degeneration encompassing neuron loss, and the level of gliosis (Vonsattel et al. 1985; Vonsattel and DiFiglia 1998). Recent advancements in in vivo MRI analyses of HD patients’ brains have unveiled early anomalies. Changes in the size and shape of the basal ganglia, cerebral cortex, and various other regions have been detected years before the manifestation of symptoms. This emerging insight has been documented by studies such as Reading et al. (2005) and Rosas et al. (2005).
1.2.3.3 Mechanisms of Neuropathology The intricate mechanisms underpinning neuronal cell death in the context of HD remain shrouded in mystery. The exact triggers behind this cellular decline have yet to be fully elucidated. Recent investigations utilizing advanced neuroimaging techniques have provided valuable insights. They reveal a progression of striatal atrophy that intensifies as the clinical onset of the disease draws nearer. Intriguingly, these studies have demonstrated the potential to predict the onset of clinical symptoms with a remarkable accuracy of around 2 years (Aylward et al. 2004; Bohanna et al. 2008). Neuropathological changes can occur up to 10 years before clinical diagnosis. Even though HD only involves a single gene mutation, it has incredibly complicated genetics. According to the results of gene microarray investigations on both postmortem HD tissue and the enlarged CAG repeat of the HTT gene, many
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additional genes are likely to interact with the HTT gene and rodent models of HD (Hodges et al. 2006; Luthi-Carter et al. 2000). These conversations result in a complicated set of criteria, which could include oxidative stress, alterations in neurotransmitters, excitotoxicity, transcriptional dysregulation, and disintegration of vesicular and cellular transport mechanisms in the cerebral cortex and striatum neurons as well as other areas throughout the brain (Cattaneo et al. 2001; Rosas et al. 2008; Thu et al. 2010). Among the neural populace residing in the striatum, the medium spiny neurons take center stage as the most susceptible to the ravages of disease, with a special focus on the striatopallidal subgroup. This particular subset, enriched with enkephalin, exhibits a distinct vulnerability. Nonetheless, the extent of neuron loss within these ranks showcases a noteworthy variability, particularly concerning the delicate delineations between the striosome and matrix compartments. As per the findings of the investigators, a significant hallmark of the phenotypic changes seen in HD lies in the realm of cortical dysfunction. Intriguingly, this dysfunction might manifest even before the actual demise of cells, primarily attributable to disruptions in cortical synaptic activity (Cepeda et al. 2007; Cummings et al. 2009). Adding another layer to the complexity, the degeneration of striatal neurons appears to be intrinsically linked to the impaired performance of their corticostriatal counterparts. This intricate interplay suggests that the malfunctioning corticostriatal neurons could potentially trigger the anterograde neurodegeneration observed in the striatal region. Furthermore, insights gleaned from studies utilizing transgenic mice have unveiled the involvement of abnormal glutamate receptor functions within the cerebral cortex. These aberrations have been directly associated with the emergence of behavioral and motor deficits. Notably, alterations in both the structure and the function of the cortex serve as harbingers, indicating the onset and intensity of these behavioral impairments (Laforet et al. 2001; Andre et al. 2006). Further exploration through a unique avenue involves the use of conditional mouse models, wherein the expression of mHtt is controlled specifically in either cortical or striatal cells. Intriguingly, this nuanced approach has unveiled a pivotal role of malfunctioning cortical neurons in the development of pronounced behavioral and motor deficits. This significant revelation is aptly demonstrated in the research (Gu et al. 2007). Expanding the horizon, the insights drawn from other transgenic mouse investigations, notably those conducted by Gu et al. (2005) and Spampanato et al. (2008), highlight connections between the dysfunction of the cerebral cortex’s interneurons and the misfire of cortical projections, and the subsequent emergence of HD. These in-depth studies collectively offer a compelling accumulation of mechanistic evidence, firmly establishing the cortex’s centrality in initiating and nurturing the HD phenotype. Notably, the failure of corticostriatal neurons stands out as a pivotal pivot in the intricate pathophysiology of the HD-affected forebrain. Several notable studies (Cepeda et al. 2007; Strand et al. 2007; Zuccato and Cattaneo 2007) have converged on a significant finding: the malfunctioning of the growth factor BDNF within glutamatergic cortico-striatal pyramidal neurons carries
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implications beyond just their own demise. It seems this dysfunction triggers a chain reaction, where either these pyramid-shaped neurons meet their demise or they suffer from impaired firing, culminating in an excessive release of glutamate. This surplus of glutamate, in turn, spells doom for neighboring striatal neurons, leading to their untimely demise. Additionally, genetic research demonstrates that each subtype of neuron in the various cerebral cortex regions has a unique genetic expression profile that defines it (Molyneaux et al. 2007). This genetic individuality underscores the notion that the problematic HTT gene, when mutated, might engage in distinct interactions with neurons throughout the brain. Notably, these interactions could exhibit a pronounced dissimilarity, particularly with specific cell types scattered across different zones of the cerebral cortex and basal ganglia. This intricate interplay could be a pivotal factor contributing to the process of degeneration that characterizes HD. The implications of this could extend to the realm of human brain vulnerability, with the forebrain bearing the brunt of this vulnerability due to the remarkable diversity seen within its various sectors. This interplay between regional and cellular intricacies adds depth to the understanding of the differential impact of HD within the forebrain areas. HD’s neuropathology is continually being reviewed. The most recent research has demonstrated that the neurodegeneration is exceedingly varied throughout the brain. Although the basal ganglia and cerebral cortex have the most severe pathology, the narrative of degeneration unfolds along a spectrum that encompasses more intricate details. Within the striatum, for instance, this degenerative tale paints a complex picture, differentiating between the striosome and matrix compartments. This divergence in degeneration nuances our understanding of how the disease orchestrates its effects within this brain region. Neuronal degeneration does not follow a uniform script but rather dances to an irregular rhythm across this cortical landscape. This variability in the distribution of degeneration intertwines with a parallel surge in gliosis, and areas of the brain outside of the basal ganglia and cortex including the cerebellum, thalamus, hypothalamus, and brainstem still need further study. Moreover, our understanding has expanded to encompass a myriad of inputs converging upon the striatum, each one newly unveiled. Among these, revelations are pathways like the hyperdirect connection from the cortex to the subthalamic nucleus (Nambu et al. 2002), the enigmatic thalamic intralaminar nuclei (Smith et al. 2004), and the intricate feedback loops stemming from the globus pallidus externa (GPe). These revelations herald a complexity that resonates through the basal ganglia pathways, weaving an intricate tapestry of interactions. Yet, the challenge that looms large is to weave together this intricate pattern of heterogeneity with the altered genetic makeup carried by the mutant genotype. This genetic anomaly casts a net of variable effects on gene expression profiles across the vast expanse of the human genome. The very mosaic of HD symptomatology, with its diverse clinical manifestations, finds its counterpart in the mosaic of neurodegeneration. This intricate symphony of cell demise and pivotal pathways unfurls uniquely across the mosaic of brain regions,
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etching a signature that distinguishes one individual from another in the face of this complex disorder.
1.3 Cerebrovascular Diseases Cerebrovascular diseases (CVDs) are a group of illnesses that affect the blood arteries that carry oxygen and nutrients to the brain. A stroke, the third most common cause of death globally, can result from these conditions. Seizures, headaches, confusion, memory loss, and difficulty speaking or understanding speech are just a few of the major health issues that the CVDs can bring on. Stroke is the most prevalent kind of CVD. A blood artery in the brain that is blocked or ruptures to reduce or stop the passage of oxygen and nutrients to the brain is the cause of a stroke. This can result in the death of brain tissue and cause severe neurological issues like paralysis, speech loss, memory loss, difficulties in walking, and difficulty in focusing. AVMs are tangles of blood vessels that can burst and cause bleeding in the brain. Other types of cerebrovascular diseases include carotid artery disease, which is the narrowing of the carotid artery leading to the brain, and subarachnoid hemorrhage, which is bleeding in the space between the brain and the skull. Cerebral aneurysms are bulging or weak spots in the walls of an artery in the brain. Early detection and intervention can lessen stroke risk, enhance quality of life, and lessen disability.
1.3.1 Stroke A stroke is a disorder where the blood supply to the brain is suddenly cut off, which causes cell death and subsequent tissue damage. The effects of these alterations on neurological function are described by the neuropathology of stroke, which also details the structural changes to the brain that follow a stroke. Ischemic stroke, which is the most prevalent kind, is brought on by a blockage in an artery that carries blood to the brain. A blood clot or an accumulation of fatty deposits in the arterial wall may be to blame for the blockage. Brain cells in the affected area die from a lack of oxygen when the blood supply is cut off, causing tissue damage. Additionally, the blood arteries in the region could undergo alterations, such as narrowing or broadening. This can result in more brain tissue damage and raise the possibility of having another stroke. In addition, the stroke may trigger an inflammatory response, which can harm the brain’s tissue even more. Scar tissue may develop as a result of this inflammation, which could result in additional neurological problems. The neurological symptoms that are experienced depend on the part of the brain that was impacted by the stroke. Paralysis, trouble speaking, loss of sensation, and visual problems are some of the typical stroke symptoms. Neurological function may be significantly impacted by the complicated neuropathology of stroke. Ischemic stroke and hemorrhagic stroke are the two main forms of stroke, and they both have unique neuropathological characteristics.
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Acute Ischemic Stroke An obstruction or blockage of a blood artery supplying the brain results in an ischemic stroke. Cellular damage occurs as a result of the reduced oxygen and nutrition delivery to the damaged brain tissue caused by the absence of blood flow. The following are the neuropathological signs of an ischemic stroke: Infarction: An infarct, which is a region of brain tissue that is necrotic or dead, is created as a result of an ischemic stroke. Normal coagulative necrosis in the infarcted area is characterized by shrunken, eosinophilic (pink-staining) neurons, and loss of cellular features (Pantoni 2010). Edema: Edema, or the buildup of fluid in the brain tissue surrounding the infarcted area, is a common complication of ischemic stroke. Ion pump malfunctions in neurons and glial cells result in intracellular water accumulation, which causes cytotoxic edema. Vasogenic edema is caused by increased blood–brain barrier permeability, which enables fluid and proteins to flow into the extracellular space. Increased intracranial pressure and subsequent brain injury can result from edema (Ropper et al. 2014). Reactive gliosis: Astrocytes and microglia get activated and go through reactive gliosis in response to ischemia injury. A glial scar is created when reactive astrocytes multiply and move towards the infarcted region. The indigenous immune cells in the brain known as microglia also become active and support the inflammatory response. Changes in cellular shape, altered gene expression, and the discharge of inflammatory mediators are all part of the intricate process known as reactive gliosis (Iadecola and Anrather 2011). Neuronal alterations: Initially, reversible changes may occur in neurons in the penumbra, the area surrounding the infarcted area. These consist of nuclear pyknosis, cytoplasmic eosinophilia, and neuronal swelling. But persistent ischemia can cause neuronal damage and even death. The length and severity of the ischemic insult, collateral blood flow, and individual variations in neuronal sensitivity all affect neuronal injury in the penumbra (Love 2006). Vascular changes: Different vascular changes may be brought on by ischemic stroke. Blood artery lining endothelial cells may expand, impairing their ability to function normally. It is possible to develop fibrin and necrotic debris deposits inside vessel walls, which is known as fibrinoid necrosis. It is also typical for a thrombus to form inside the damaged blood arteries, aggravating the ischemic injury (Pantoni 2010). Hemorrhagic stroke: Hemorrhagic stroke happens when there is bleeding into the subarachnoid space or into the brain parenchyma (intracerebral hemorrhage). Blood causes immediate harm to the brain tissue in the area around it. The following are some of the neuropathological signs of hemorrhagic stroke: Hemorrhage: Blood extravasation into brain tissue or the subarachnoid space is what gives hemorrhagic stroke its name. Blood buildup affects natural brain architecture and directly damages it mechanically. Formation of a hematoma: Blood that has been extravasated builds up. The hematoma may compress or push nearby brain regions, inflicting additional
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damage, depending on the site and the extent of the hemorrhage (MacLellan et al. 2010). Blood in the brain tissue causes toxicity and oxidative stress, which in turn causes neuronal injury and death in the surrounding tissue. Iron and hemoglobin, blood breakdown products that can cause inflammation and free radical production, can harm secondary neurons (Keep et al. 2012). Vascular alterations can occur inside the damaged blood vessels as a result of hemorrhagic stroke. Blood leaks out of blood vessels as a result of blood vessel walls rupturing. Vascular integrity is also affected by inflammation and the development of microthrombi (Poon et al. 2014).
1.3.2 Traumatic Brain Injury A head injury can result in traumatic brain damage (TBI), a serious and perhaps fatal disorder. It is the main cause of death for people between the ages of 1 and 45 in the United States, as well as a major contributor to disability. TBI can be brought on by a number of events, such as assaults, falls, sports-related injuries, physical trauma, and car accidents. TBI-related neuropathology is a complicated and developing field. Axonal injury, ischemia, and neuronal necrosis are some of the neuropathological alterations connected to TBI. Rapid head deceleration results in axonal stretching and possible axonal function disruption, which causes axonal injury (Saatman et al. 2009). Ischemia is brought on by decreased cerebral perfusion, which can happen as a result of the primary consequences like elevated intracranial pressure or the secondary ones like the direct mechanical force of the injury (Kinoshita 2016). Direct mechanical injury to neurons as well as subsequent metabolic and inflammatory consequences lead to neuronal necrosis (Mckee and Daneshvar 2015). In addition to these immediate effects of TBI on the brain, neuropathological analysis can also reveal long-term impacts. Axonal damage, neuronal cell death, white matter injury, gliosis, and vascular alterations are a few of these. A number of neurological abnormalities, including cognitive impairments, motor deficits, and seizures, can be brought on by axonal injury and neuronal cell death. Axonal shearing causes white matter damage, which can lead to lesions in the white matter and myelin loss (Bramlett and Dietrich 2015). Gliosis is an inflammatory reaction to damage that can result in scarring, increased vascular permeability, loss of neurons, and other complications. Increased blood–brain barrier permeability is one of the vascular alterations that can cause cerebral edema and brain swelling (Burda and Sofroniew 2014; Bernardo-Castro et al. 2020). TBI’s long-term consequences might progress over time and result in neurological disability that cannot be cured. For proper care and support of those with TBI, it is essential to comprehend the neuropathology connected to TBI.
1.3.2.1 Concussion A concussion is the most frequent type of traumatic brain injury (TBI), which is typically brought on by a direct hit on the head or body and results in a brief disruption of regular brain activity. Concussion neuropathology includes a variety of
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diverse processes, such as cellular damage, metabolic alterations, and mechanical trauma. Mechanical trauma, which results from a direct impact to the head or body, is the main cause of concussions. It can shear or stretch axons, harm blood vessels and nerve cells, and disturb the normal structure of the brain. Confusion, dizziness, and memory loss are just a few of the physical and cognitive symptoms that can occur from this (Giza and Hovda 2014). An increase in pro-inflammatory cytokines is one of the metabolic modifications brought on by concussion, and these modifications can exacerbate excitotoxicity, decrease energy metabolism, and increase oxidative stress. These procedures have the potential to impair regular brain activity, cause brain cell death, and result in long-term harm to the brain. Another type of neuropathology connected to TBI is cellular injury (Bramlett and Dietrich 2015). The brain is subjected to a variety of physical stresses during a concussion, which may directly harm the cells. Loss of neurons, glial cells, and other types of cells may occur from this, which may cause cognitive, physical, and psychological deficits (Mckee and Daneshvar 2015). In conclusion, mechanical trauma, metabolic alterations, and cellular damage are just a few of the distinct processes that contribute to concussion’s neuropathology. These processes can have negative effects on a person’s health and well-being and can result in long-term deficits. When a concussion is suspected, it is critical to recognize the warning signs and symptoms and get medical assistance.
1.3.2.2 Contusion Bruises or contusions are a frequent type of injury found in TBI. Direct brain trauma leads to localized damage to the brain tissue and surrounding structures, which is how they are brought on. Both coup and contrecoup injuries can be categorized as contusions. Contracoup injuries happen on the side of the brain opposite from the hit site, whereas coup injuries happen at the point of impact (Mckee and Daneshvar 2015; Adatia et al. 2021). The size, position, and depth of contusions are other classifications that can be made. Small contusions are normally superficial; however, large ones can be deep and affect the deeper structures or the underlying white matter (Pellot and De Jesus 2023). Depending on the extent of the injury, several neuropathologies are associated with contusions. A localized area of swelling, bleeding, and inflammation is usual in mild contusions. The blood–brain barrier frequently breaks down along with this, which can cause edema and additional harm to the surrounding tissue. More serious contusions may result in tissue necrosis and axon loss, which can impair neuronal function and ultimately cause death (Chodobski et al. 2011). Different long-term impacts on the brain from contusions are possible. The size, location, and depth of the injury can all affect how much harm is done. While larger, deeper contusions can result in more serious impairments, smaller, more superficial contusions may produce lesser symptoms (Galgano et al. 2017). White matter loss can impair the brain’s ability to transmit messages, which can result in deficiencies in cognition, behavior, and motor function. Even more severe abnormalities, such as convulsions and movement disorders, can result from damage to deeper regions, such as the basal ganglia (Schmahmann et al. 2008; Wang et al. 2016). There are indirect effects of brain contusions in addition to the direct effects. Inflammation and an increase in intracranial pressure brought on by contusions may result in
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additional brain injury. Free radicals, which harm neurons and worsen brain function, can increase as a result of contusions. In conclusion, contusions are a frequent type of TBI injury, and the size, location, and depth of the injury might affect the neuropathology. Both direct and indirect brain damage can result from concussions, including damage from inflammation, elevated intracranial pressure, and free radicals. Therefore, to reduce the long-term repercussions of the injury, it is crucial to accurately identify and treat contusions.
1.4 Systemic Diseases Systemic diseases are those that affect a wide range of organs and tissues, causing a range of neurological symptoms. Neuropathological changes that can be seen in systemic diseases include inflammation, ischemia, and axonal damage (Bowley and Ropper 2015). According to Straub and Schradin (2016), systemic disorders frequently exhibit inflammation, which can kill nerve cells and cause the release of hazardous free radicals and other toxins. Ischemia is a decreased supply of blood to the brain, which can result in cell death and neurological problems. Axonal damage is another common finding in systemic diseases and is caused by axonal transport deficits, which may lead to impaired nerve conduction (Haines et al. 2011). Neurodegenerative diseases are a subset of systemic diseases that affect the activity of the nervous system. These diseases are characterized by progressive neuronal loss that can cause a variety of neurological indices, such as memory loss, impaired motor coordination, and difficulty speaking or understanding language. Common neurodegenerative diseases include AD, PD, and HD. Neuroinflammatory diseases are another type of systemic disease that can affect the nervous system. These diseases are characterized by an abnormal immune response, which can lead to inflammation and nervous system damage (Ransohoff et al. 2015). Myasthenia gravis, Guillain–Barre syndrome, and multiple sclerosis are a few examples of neuroinflammatory illnesses. Finally, there are a number of systemic disorders that can distress the peripheral nervous system. These illnesses can cause a variety of symptoms, such as numbness, tingling, and weakness. Common peripheral neuropathies include diabetic neuropathy, carpal tunnel syndrome, and hereditary neuropathy. In conclusion, various systemic disorders can affect the nervous system. Neurological indices can result from a range of neuropathological events, including inflammation, ischemia, and axonal. Neuroinflammatory and neurodegenerative illnesses can cause progressive neuronal loss and abnormal immune responses, which can lead to further damage and disability. Finally, there are a number of systemic diseases that can influence the peripheral nervous system and lead to numbness, tingling, and weakness.
1.4.1 Multiple Sclerosis Multiple sclerosis (MS) represents an autoimmune and inflammatory ailment affecting the CNS. It is characterized by the degeneration of the protective myelin sheath encompassing nerve cells. This pathology results in the formation of lesions in the
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white matter of the brain and spinal cord, which leads to a wide range of physical and cognitive symptoms, including motor impairment, visual disturbances, fatigue, and cognitive decline (Lemus et al. 2018). The precise cause of MS remains incompletely comprehended, although it is believed to arise from a blend of genetic predisposition and environmental influences. Studies have demonstrated that specific genetic variations, such as HLA-DR15, are linked to an elevated susceptibility to MS (Masterman et al. 2000; Schmidt et al. 2007). Furthermore, external factors like viruses, toxins, and dietary elements might also contribute to its onset. At its core, the pathology of MS originates from an immune-mediated assault targeting the myelin sheath. This assault is believed to be incited by an antigen present on the myelin sheath. In this process, the immune system erroneously identifies the myelin sheath as an alien intruder and mounts an attack against it. This aggressive immune response leads to the degradation of the myelin sheath, giving rise to lesions within the white matter of the brain and spinal cord (Ghasemi et al. 2017). The lesions caused by MS can vary in size and location and can be either active or inactive. Active lesions are characterized by an inflammatory process and are associated with clinical symptoms. Inactive lesions, on the other hand, are not associated with any inflammation or clinical symptoms. The destruction of the myelin sheath caused by MS leads to a wide range of physical and cognitive indices. Motor disturbances, such as weakness, spasticity, and incoordination, are common. Visual anomalies like blurred vision, double vision, and even blindness can manifest in MS. Profound fatigue also stands as a prevalent symptom. Cognitive functions can be impacted, leading to memory lapses and challenges in concentration. To sum up, MS stands as an autoimmune inflammatory disorder affecting the CNS, marked by the degradation of the myelin sheath and the emergence of lesions in the brain and spinal cord’s white matter. Although the precise origin of MS remains elusive, it is presumed to arise from a confluence of genetic and environmental influences. The pathogenic process behind MS gives rise to a diverse array of physical and cognitive manifestations.
1.4.1.1 Neuroinflammation: Unleashing the Disruption Within the Brain In the context of MS, a proposed theory akin to animal models suggests that the initial phase of inflammation in the brain involves the migration of activated T cells across the blood–brain barrier (Wekerle 1998). This serves as a crucial initial step in the cascade of events leading to brain inflammation. Within this process, activated T helper 1 (Th1) cells play a pivotal role. These cells are known to stimulate local or bloodstream-distributed macrophages, inciting them to target myelin and subsequently release potential autoantigens specific to the CNS. This intricate interplay between Th1 cells and macrophages contributes to the progression of inflammation. The actively demyelinating lesions’ characteristic of MS demonstrates the presence of Th1-related cytokines, including TNF-α, IFN-γ, lymphotoxin-α, and IL-2. Notably, heightened levels of TNF-α show a positive correlation with disease activity and the impairment of the blood–brain barrier (Merrill’s 1992). These observations furnish compelling in vivo evidence
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underscoring the involvement of T cells of the Th1 phenotype in the formation of lesions within the MS context. Scientific observations have revealed the presence of lymphocytes beyond the realm of CD4+ helper cells at the sites of MS lesions. Notably, CD8+ cells, predominantly localized in the perivascular areas, have emerged as key actors in tissue destruction, surpassing the direct involvement of CD4+ cells. Distinguishing this phenomenon, it is noteworthy that CD8 cells exhibit a more pronounced clonal expansion compared to their CD4 counterparts within the context of MS plaques (Babbe et al. 2000; Steinman 2001). Strikingly, the proportion of CD8+ cells demonstrates a stronger correlation with the severity of acute axonal damage than the proportion of CD4+ cells (Bitsch et al. 1998).
1.4.1.2 Unraveling Mechanisms Behind Primary Myelin Loss Scientific investigations involving extensive biopsy and autopsy samples from individuals with MS have shed light on the intriguing possibility that distinct processes might underlie myelin breakdown in different patients (Lucchinetti et al. 2000a). Actively demyelinating lesions present a unique opportunity to delve into the mechanisms of demyelination. Notably, various myelin proteins, including minor ones like myelin oligodendrocyte glycoprotein (MOG), exhibit immunoreactivity within the infiltrating macrophages that densely populate these lesions (Bruck et al. 1995). Upon analyzing 235 actively demyelinating lesions, four distinctive patterns of myelin breakdown have come to light. Across all these patterns, a common thread is the presence of an inflammatory response dominated by T cells and macrophages. In the case of patterns I and II, these animal models of autoimmune encephalomyelitis successfully replicate the demyelination process. Pattern II involves antibodies and complements as culprits, while pattern I sees demyelination specifically induced by toxins like TNF-α or reactive oxygen species secreted by macrophages. Despite associations between antibodies targeting several myelin proteins and MS, the precise pathogenic role of these antibodies remains elusive. However, anti- MOG antibodies have surfaced in both the serum and the cerebrospinal fluid of a small subset of MS patients (Reindl et al. 1999). Interestingly, their presence during disease initiation might serve as a predictor for subsequent relapses, a notion suggested by communication from Reindl and Berger. Encouragingly, isolated instances have illustrated the therapeutic benefits of plasma exchange for certain patients, hinting at the potential pathogenic significance of anti-myelin antibodies within a subgroup of patients (Weinshenker et al. 1999). When it comes to lesions categorized as patterns I and II, the primary focus of the destructive process lies upon the myelin sheath itself. Conversely, in lesions categorized as patterns III and IV, indications suggest that the degeneration encompasses the oligodendrocyte. Notably, the animal models for inflammatory demyelination have yet to effectively replicate lesions akin to patterns III and IV. Pattern III lesions exhibit peculiarities like encircling inflamed arteries with preserved myelin rings, accompanied by ill-defined borders and an early loss of myelin-associated glycoprotein (MAG) within nascent active lesions.
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It is interesting to note that acute white matter strokes and virus-induced illnesses of the white matter both occasionally exhibit primary loss of MAG (Kornek and Lassmann 2003). These preliminary findings point to ischemia as having a pathogenic function in a subgroup of MS patients. By a process other than traditional apoptosis, oligodendrocytes in the periplaque white matter in pattern IV are degenerating. However, in these uncommon situations, there is a small inflammatory response that is accompanied by significant tissue damage. With the exception of pattern IV, which has sporadically been observed in individuals with primary progressive MS, the diverse demyelination patterns have not yet been definitively associated with specific clinical presentations in patients with conventional chronic MS. However, patterns II and III exhibit connections to particular clinical manifestations in more aggressive disease courses. Specifically, pattern III lesions have been identified in cases of Balo’s concentric sclerosis and Devic’s neuromyelitis optica, while pattern II lesions are consistently present in all instances of Devic’s neuromyelitis optica, as elucidated by Lucchinetti et al. (2000b). Furthermore, distinctions might exist in how the brain responds to injury between individuals with MS and those without the condition. This topic is comprehensively discussed in a review by Compston (1998). Notably, a multitude of genes, particularly those associated with immune response regulation such as MHC II genes, T cell receptor genes, and immunoglobulin heavy chain genes, have been implicated in the susceptibility to MS (Compston 1998). Intriguingly, beyond predisposition to the disease, genetic factors might also play a role in shaping the disease’s intensity. This is exemplified by the Apo E allele 4, as demonstrated by Fazekas et al. (2001). Additionally, genetic elements could influence the timing of disease onset, adding another layer of complexity to the interplay between genetics and MS pathogenesis. But in this succinct summary, we focus on the potential causes of demyelination in MS. In conclusion, one distinguishing aspect of MS is inter- but not intra-individual variability with regard to demyelination. This could have significant effects on clinical practice because different patterns might call for different therapeutic approaches. The foundation for defining paraclinical markers of lesion subtypes will be provided by MRI correlates of histologically identified lesions (Bitsch et al. 2000; Bruck et al. 1997) as well as CSF markers (Reindl et al. 1999).
1.4.1.3 Unveiling the Neural Injury: Axonal Impairment in Multiple Sclerosis The depolarization of the axonal plasma membrane is thought to be the cause of conduction block, which underlies acute neurological impairment in relapse (Youl et al. 1991). In the context of demyelination, the redistribution of ion channels within the affected axon can lead to the restoration of conduction, thus offering a degree of reversibility to this impairment (Moll et al. 1991). However, the persistence of axonal dysfunction and subsequent loss has been closely tied to irreversible impairment, gradually accumulating over time (Davie et al. 1995; De Stefano et al. 1998). Consequently, despite being somewhat overlooked for a considerable duration, the investigation of axonal damage and loss has garnered significant attention in recent years (Kornek and Lassmann 1999). A substantial portion of acute axonal damage manifests early in the process of lesion formation, most
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prominently observed in actively demyelinating plaques, as definitively demonstrated in studies by Bitsch et al. (2000) and Kornek et al. (2000). This acute axonal injury, intricately linked to the inflammatory response, may contribute to ongoing fiber degeneration, extending even to long-standing dormant lesions. In these dormant demyelinated plaques, a noticeable reduction in fiber density of up to 75% occurs, while the decline in axonal density within actively demyelinating lesions is multifaceted and in part attributed to inflammatory edema (Mews et al. 1998). Extensive loss of nerve fibers, a characteristic finding in MS, plays a pivotal role in contributing to chronic clinical deficits. Notably, nerve cell loss exceeding 50%, as seen in classic neurodegenerative disorders like ALS, is considered clinically significant (Trapp et al. 1999). However, in the context of remyelinated shadow plaques, the extent of axonal damage and subsequent density loss is minimal. Here, myelinating oligodendrocytes might provide trophic support to the axon, and the myelin sheath itself could potentially shield it from the inflammatory mediators emanating from the plaque site. Reversible NAA reduction in MR spectroscopy, a measure for axonal integrity, may be a sign of acute axonal dysfunction (De Stefano et al. 1998). In contrast, persistent Th1 hypointense lesions, or so-called “black holes,” may exhibit significant axonal damage (Bitsch et al. 2001), which may also be reflected by an irreversible drop in NAA within and around MS plaques (Matthews et al. 1998). Axonal damage and loss are a constant aspect of MS; however, the degree varies. On the one hand, the plaque’s demyelinating activity might help to explain this. On the other hand, this could also be the result of intra-individual variation in axonal pathology, which in some patients manifests as early, severe axonal damage and in others, as modest harm even in long-standing plaques.
1.5 Conclusion The conclusion of neuropathology in neurological disorders is that neuropathology is crucial to comprehending the causes and remedies of neurological disorders. Neuropathologists can determine the root cause of an illness and create treatments to assist in the management of symptoms by examining changes in the structure and operation of the nervous system. Neuropathology is crucial for identifying neurological disorders and forecasting how therapies will work. Additionally, neuropathology might suggest new preventative and therapeutic approaches as well as shed light on the mechanisms underlying the development of neurological illnesses. Further study and investigation are needed in the complicated, the fast developing field of neuropathology to better comprehend and treat neurological illnesses.
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Head Trauma: Etiology, Pathophysiology, Clinical Manifestation, and Biomarkers Liam Goldman, Mario P. Espinosa, Manish Kumar, Luca H. Debs, Fernando L. Vale, and Kumar Vaibhav
Abstract
Head trauma often results in traumatic brain injury (TBI) which is a prominent cause of morbidity and mortality among children and young adults in the United States of America. Head trauma is most common because of motor vehiclerelated injuries, falls, and assaults. These injuries have both short- and long-term sequelae that affect roughly 5.3 million Americans per year and result in a heavy economic burden estimated at $37.8 billion per year (Matney et al., Traumatic brain injury: a roadmap for accelerating progress, National Academies Press, Washington, DC, 2022). While the mechanisms of the primary insult are understood in depth, the long-term effects due to secondary brain injury are currently being widely studied. Due to the vast economic and social impact of head trauma, much effort by healthcare systems and researchers is being carried out to under-
Liam Goldman and Mario P. Espinosa contributed equally with all other contributors. L. Goldman · M. P. Espinosa · M. Kumar · L. H. Debs · F. L. Vale Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA K. Vaibhav (*) Department of Oral Biology and Diagnostic Sciences, Center for Excellence in Research, Scholarship and Innovation, Dental College of Georgia, Augusta University, Augusta, GA, USA Transdisciplinary Research Initiative in Inflammaging and Brain Aging (TRIBA), Augusta University, Augusta, GA, USA Brain Injury, Senescence and Translational Neuroscience Lab, Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_2
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stand the pathophysiology, to develop treatments, and to enact preventative actions to reduce the global burden of the traumatic injuries to the head. These endeavors have resulted in an overall reduced deaths and TBI-related hospitalizations. In this contemporary chapter, we dissect different etiologies and the pathophysiology of brain injury that result from head trauma. In addition, we address the modern diagnostic techniques, treatments, and current traumatic brain injury research. Keywords
Head trauma · Traumatic brain injury (TBI) · Etiology · Pathophysiology · Global burden · Mortality · Healthcare · Biomarkers · Clinical manifestation
2.1 Introduction Head trauma is a common occurrence around the world. In the United States of America, head trauma leading to traumatic brain injury (TBI) is a leader in the causes of morbidity and mortality among children and young adults (Dewan et al. 2018). Approximately 5.3 million Americans are affected by trauma to the head and about 176 Americans die from TBI-related injury daily. As a result, the United States bears a heavy economic burden of approximately 37.8 billion (Roozenbeek et al. 2013; Matney et al. 2022). Further, the CDC reports that 15% of all 15 million American high-school students have reported concussions within a given year (Ilie et al. 2013). Under a general classification of accidental or nonaccidental, the resulting head injury can be further categorized as penetrating, blunt, or blast. Resultant brain injuries other than brain trauma during birth are often referred as the acquired brain injury (ABI) (Goldman et al. 2022). While most ABIs are benign and mild in nature, TBI often results in cognitive, motor, sensory, and language deficits. Head trauma is commonly caused as a result of motor vehicle-related injuries, falls, and assaults (Roozenbeek et al. 2013). While the mechanisms of the primary insult are fairly understood, the long-term effects due to secondary brain injury are currently being widely studied. In an effort to reduce the global burden and socioeconomic impact of head trauma, much effort by healthcare systems and researchers is being carried out to understand pathophysiology, develop treatments, and enact preventative actions. These clinical, translational research science, and public health endeavors have resulted in an overall reduction in TBI-related deaths and hospitalizations. Since 1980, TBI-related deaths have declined by 20% and TBI-related hospitalization rates by 50% (Thurman et al. 1999). In this chapter, we acknowledge the different etiologies, pathophysiology, and clinical manifestations of injury that result from head trauma. Moreover, we have discussed the clinical importance of TBI biomarkers and the future treatment strategies for patients suffering from head trauma.
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2.2 Etiologies of Head Trauma Injuries to the head are divided into two general categories: accidental and non- accidental trauma (NAT; Fig. 2.1). Head injury that has an accidental cause, rather than being caused by a disease process or a longstanding medical condition, is called accidental head trauma (Paul and Adamo 2014). The top three leading causes of preventable injury-related death—poisoning, motor vehicle, and falls—account for over 86% of all preventable deaths. Other preventable causes of death—including suffocation, drowning, fire and burns, and natural or environmental disasters— account for more than 5% of the total (GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators 2019). Common examples of accidental head trauma include falls and motor vehicle collisions (MVCs). Falls are the foremost cause of TBI and account for roughly half of all TBI-related hospitalizations. In 2019 alone, there were three million emergency department visits for falls in patients 65 years old or above (Paul and Adamo 2014; GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators 2019). Falls, especially in the elderly population, result in significant morbidity and account for an annual 50 billion dollars in medical costs (Gelineau-Morel et al. 2019). Accounting for 17.3% of all TBIs, MVCs are the second leading cause of head trauma. These accidents encompass automobile and motorcycle accidents in addition to pedestrians being struck by vehicles (GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators 2019). NAT is a purposefully inflicted injury that occurs mostly to the skin and soft tissue, but approximately one-third of NATs results in fractures. A thorough examination is imperative to describe this type of injury. Non-accidental injury results in unexplained visceral injuries, retinal hemorrhages, and spiral fractures in bone or femur fractures in a child (Gelineau-Morel et al. 2019). The most common signs caused by NAT are bruises, abrasions, lacerations, scratches, soft tissue swellings, strap marks, hematomas, thermal burns, and bites. Abusive head trauma (AHT), also known as shaken
Fig. 2.1 General classification of head trauma. Head trauma can be classified into two types— accidental and non-accidental. Accidental head trauma occurs because of motor vehicle or fall accidents. Poisoning is also a common cause for this type of trauma. Non-accidental includes birth defects and abusive hit to the head. (Created with BioRender.com)
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baby syndrome, remains the most common cause of death in the victims of NAT and usually occurs during the first 12–18 months of life (Smith et al. 2019). These two general groups (i.e., accidental and non-accidental) are further broken down into three categories describing the type of head trauma caused: blunt, penetrating, and blast (Hicks et al. 2010). Blunt force head trauma is the most common form and is caused by simply any kind of blow to the head by a blunted object that does not pierce or penetrate the skull. A few examples of these injuries include sports injuries, motor vehicle collisions, and punches. Blunt force trauma results in a wide variety of clinical outcomes depending on the strength and location of the trauma (Thurman et al. 1999). Penetrating head trauma occurs when a foreign object pierces through the scalp and skull, entering the brain tissue, and is associated with significantly increased mortality and morbidity, especially among the young population. The severity of clinical outcomes of patients that suffer penetrating trauma to the head depends on five factors: circumstances of the event; size and type of penetrating object; energy and speed of entry; intracranial path and location; comorbid injuries. Neurosurgical intervention is imperative for life-saving treatment (Sandsmark 2016). Blast injury is most commonly studied and encountered in soldiers. Unlike the collisions or impacts which are more commonly associated with head trauma, head trauma produced by blasts is a result of shock waves. The primary injury to internal organs from blasts is caused by an acute over-pressurization of tissue. Concussions are the most common outcome of head trauma sustained from an explosion (Sandsmark 2016). Moreover, the severity of TBI can be classified as mild, moderate, or severe (Fig. 2.2) (Eken et al. 2009). The American Congress of Rehabilitation Medicine (ACRM) defines TBI as mild (mTBI) as manifested by one of the four following criteria: (1) period of unconsciousness; (2) amnesia; (3) any alteration of mental state (disorientation, confusion, etc.); and (4) focal neurological deficit. Colloquially, this form of injury is known as TBI (Najem et al. 2018). According to the National Institute of Neurological Disorders and Stroke, a person with moderate or severe TBI may have additional symptoms associated with the head injury such as nausea or vomiting, seizure, and/or pupil dilation (Sussman et al. 2018). These symptoms can all be determined quickly along the bedside using entrusted assessment tools. First published in 1974, the Glasgow Coma Scale (GCS) measures the degree of neurological insult (Teasdale and Jennett 1974). It is commonly used among medical and trauma patients, giving the physician an objective score describing the level of impaired consciousness (Teasdale et al. 2014). The score evaluates different aspects of a patient’s awareness and responsiveness. The patient’s ability to open their eyes, perform motor commands, and respond verbally is independently scored and then summed for an overall severity score (Teasdale and Jennett 1974). The severity of brain injury can be broken down into three categories as defined by the GCS score: (a) 13–15 (mild); (b) 9–12 (moderate); (c) 3–8 (severe) (Fig. 2.2). The GCS is featured in many guidelines and assessment scores such as Trauma Life Support, and Brain Trauma Foundation TBI Guidelines and Advanced Cardiac Life Support (Grinnon et al. 2012). While this score has been used widely for its important clinical function, it has its own limitations. It does not take into account pre- existing medical conditions or current treatments that could be interfering with the
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Fig. 2.2 Classification of TBI severity. Traumatic brain injury can be separated into three distinct categories: mild, moderate, and severe. Each of which is comprised of certain criteria that must be met to accurately diagnose the severity of TBI. Among the most important parameters is the Glasgow Coma Scale (GCS). For example, a moderate TBI would include a patient scoring a 9–12 on the GCS, experiencing loss of consciousness somewhere in between 30 min up to a day, alteration of consciousness for more than a day, and posttraumatic amnesia for more than 1 day but less than a week (Hu et al. 2022; Healy et al. 2015). These parameters help determine the course of treatment required for these patients. (Created with BioRender.com)
patient’s capacity to respond. This shows that while GCS is an important prognostic feature, it should not be used alone to assess a patient’s TBI outcome (Teasdale et al. 1979).
2.3 Pathophysiology of TBI 2.3.1 Primary Brain Injury and Secondary Injury Neuronal tissue damage associated with TBI can be categorized into primary and secondary injuries (Fig. 2.3) (Jarrahi et al. 2020). Primary injury refers to the damage caused by mechanical forces involved at the initial moment of impact leading to focal or diffuse brain injury patterns. Focal injury is due to contact forces resulting in a skull fracture, coup contusion, subdural hematoma (SDH), and epidural hematoma (EDH), while diffuse injury is a result of inertial forces such as translational and rotational acceleration producing diffuse axonal shearing and swelling in cerebral brain tissues (Ray et al. 2002; Schmidt et al. 2004). Secondary injury, on the other hand, involves biochemical and cellular impairments as a result of the primary injury (Ng and Lee 2019). More specifically, these events advance over a span of hours to days following the TBI and are related to the release of endogenous
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Fig. 2.3 Pathophysiology of traumatic brain injury due to head trauma. Hit to the head often results into traumatic brain injury (TBI). TBI has events that start by direct impact and is termed as primary injury. It includes both focal hematoma and contusion of skull fracture. Secondary injury processes start as a consequence of primary injury in days and may continue up to months. Secondary injury includes circulatory and metabolic effects. Some of the major events in this category are excitotoxicity, mitochondrial dysfunction, apoptosis, and oxidative stress. (Created with Biorender.com)
mediators that modify cerebral blood flow, metabolism, ion homeostasis, and cellular function through their time-dependent agonistic and antagonistic functions (Ray et al. 2002; Schmidt et al. 2004; Jarrahi et al. 2020). Some of the cellular processes that will be discussed include, but are not limited to, excitotoxicity, mitochondrial dysfunction, lipid peroxidation, neuroinflammation, and apoptosis (Fig. 2.3).
2.3.2 General Stages of Cerebral Injury After TBI Cerebral injury following TBI can be outlined by certain stages in which specific pathophysiological events occur. The first stage involves the primary insult-inducing dysregulation of cerebral blood flow and metabolism. The pattern of this injury is ischemic in nature and leads to increased membrane permeability, anaerobic glycolysis, and edema formation; inadequate metabolism ultimately leads to depletion of ATP, and, subsequently, failure of energy-dependent membrane ion pumps (Werner and Engelhard 2007; Jarrahi et al. 2020). The second stage is followed by increased release of excitatory neurotransmitters such as glutamate, activation of lipid peroxidases and proteases, and other biochemical cascades that collectively lead to necrosis or apoptosis through membrane degradation of cellular and vascular structures (Werner and Engelhard 2007; Jarrahi et al. 2020).
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2.3.3 Cerebral Blood Flow TBI is characterized by cerebral hypoperfusion due to various mechanisms including morphological injury of vessels and cells, impairment of cerebrovascular autoregulation, and potentiation of prostaglandin-induced vasoconstriction (Werner and Engelhard 2007). As a result of impaired cerebrovascular autoregulation, there is no vascular homeostatic response to altered cerebral perfusion pressure (CPP) leading to the development of intracranial hypertension (Kim et al. 2012; Werner and Engelhard 2007). The imbalance between oxygen consumption and cerebral oxygen delivery results in tissue hypoxia even in the presence of normal CPP and intracranial pressure (Stiefel et al. 2006).
2.3.4 Excitotoxicity Neuronal cell death and blood–brain barrier (BBB) permeability during TBI prompts the excessive release of excitatory neurotransmitters glutamate and aspartate, and these neurotransmitters are maintained at high levels in extracellular space and cerebrospinal fluid due to impaired glutamate re-uptake transporters (Chamoun et al. 2010; Ng and Lee 2019). Hyperactivation of N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by excessive glutamate alters ion homeostasis by allowing an influx of extracellular sodium and calcium ions; this influx leads to downstream activation of other signaling molecules promoting the production of reactive oxygen species (ROS), caspases, proteases, and other proteins that induce apoptosis (Ng and Lee 2019). Additionally, the accumulation of calcium ions and ROS impedes mitochondrial functions resulting in further oxidative stress and metabolic deregulations (Ng and Lee 2019).
2.3.5 Mitochondrial Dysfunction Increased permeability and depolarization of mitochondrial membrane and reduced ATP synthesis are outcomes of excitotoxicity following TBI, which lead to the deterioration of the electron transport chain and oxidative phosphorylation (Lifshitz et al. 2004; Ahluwalia et al. 2021). As a result, cellular metabolism is blunted, and the mitochondria begin to release apoptotic proteins such as cytochrome c into the cytosol due to structural changes affecting membrane permeability (Sullivan et al. 2002; Ahluwalia et al. 2021). Through this mechanism, mitochondria can potentiate the process of apoptosis occurring after TBI.
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2.3.6 ROS and Lipid Peroxidation ROS and free radicals are byproducts of many pathophysiological processes that occur following TBI and play a role in lipid peroxidation, which impacts brain plasticity, cerebral blood flow, and immunosuppression (Ansari et al. 2008). Specifically, the buildup of calcium ions after TBI causes an increase in the production of nitric oxide (NO) which can react with free radical superoxides and forms peroxynitrite to induce oxidative damage in the brain specifically in the cortex and hippocampus (Ansari et al. 2008; Ng and Lee 2019). These ROS interact with fatty acids in membrane phospholipids causing membrane damage and increased permeability, which ultimately leads to cellular dysfunction and compromised ion homeostasis (Ng and Lee 2019).
2.3.7 Edema Edema formation is common in TBI and can be categorized into vasogenic or cytotoxic edema. Vasogenic edema refers to the functional breakdown of the endothelial cell layer of brain vessels. Cytotoxic edema, on the other hand, is characterized by intracellular fluid accumulation in brain cells caused by permeable cell membranes and failure of membranous ionic pumps rather than an attenuated endothelial wall (Werner and Engelhard 2007). Although cytotoxic edema is more common following TBI, both types play a role in increased intracranial pressure and secondary cerebral hypoperfusion (Marmarou et al. 2006).
2.3.8 Neuroinflammation TBI can induce acute neuroinflammatory cascades within 24 h of the cerebral injury by disrupting the BBB and allowing blood immune cells such as monocytes, granulocytes, and lymphocytes to enter the central nervous system (Lotocki et al. 2009; Goldman et al. 2022). Through the release of complement factors and pro- inflammatory cytokines such as TNF-α, IL-1β, and IL-6, the integrity of the BBB is further broken down and vasogenic edema ensues (Ng and Lee 2019). Many of the cytokines released play regulatory roles in activating pro-apoptotic proteins and upregulating other factors responsible for recruiting leukocytes to the injury site (Ng and Lee 2019). Chronic neuroinflammation, on the other hand, involves the accumulation of activated macrophages/microglia inducing astrogliosis for months following the cerebral injury as evidenced by white matter degradation (Johnson et al. 2013; Jarrahi et al. 2020).
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2.3.9 Necrosis and Apoptosis While necrosis is a type of cell death that may immediately occur in cases of TBI, apoptosis is programmed cell death that becomes evident over hours or days following the injury. Necrosis involves irreversible mechanical and ischemic tissue damage that is no longer metabolically viable and is subsequently recognized and cleared by immune cells (Werner and Engelhard 2007). Apoptosis involves the death of neurons that have not undergone drastic structural changes due to injury and are still morphologically intact; this process is delayed in TBI and is due to an imbalance between pro- and anti-apoptotic proteins, in addition to consistent activation of caspases and other proteases (Werner and Engelhard 2007; Jarrahi et al. 2020).
2.4 Clinical Manifestations of Head Trauma 2.4.1 Cephalohematoma Cephalohematomas as a sole presentation of head trauma in adults are very rare; however, this entity is a common presentation in neonates. Neonatal trauma at birth is an unfortunate yet fairly common incident, occurring at a rate of about 25–31 per 1000 hospital births. Injuries to the scalp of the newborn make up roughly 80% of all birthing traumas (Gupta and Cabacungan 2021). Of the different scalp injuries, cephalohematoma is a frequent manifestation of cranial trauma at birth with an incidence of 0.4–2.5% of all spontaneous vaginal births. Some risk factors include macrosomia, primigravidae, occipital-posterior or transverse-occipital position, and instrument-assisted births (Ekéus et al. 2018). A cephalohematoma results from a rupture of subperiosteal blood vessels mostly due to compression of the neonate’s cranium against the maternal pelvis or surgical forceps. The pushing force generated by the mother during delivery or traction from forceps causes a shearing force that damages emissary and diploic veins. Swelling can be appreciated on the scalp when enough blood accumulates in the subperiosteal space, lifting the periosteum of the skull. Cephalohematoma is characterized as a uni- or bilateral bulge, covering one or multiple skull bones beneath the scalp, most commonly found over the parietal bone. These injuries do not cross suture lines and there is no bruising of the skin (Parker 2005). No immediate intervention is needed as this condition is self-limited due to an increase in pressure of accumulated blood acting as a tamponade. Moreover, there is no particular diagnostic test for cephalohematoma; however, many providers suggest ultrasound, X-rays, or a computed-tomography (CT) scan if there is clinical suspicion for more serious injuries or to evaluate potential fractures (Ekéus et al. 2018). Otherwise, treatment is observational. Over the time span of a couple of weeks, the hematoma will begin to disappear. A rare complication occurs when the cephalohematoma begins to calcify, which requires surgical intervention (Kortesis et al. 2009).
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2.4.2 Subgaleal Hemorrhage Subgaleal hemorrhages (SGH) are another example of extracranial hemorrhage that is more common in neonates than adults. SGHs are much rarer in adults and are generally linked with a low rate of morbidity and mortality in them. Albeit a rare complication of spontaneous vaginal births (4 per 10,000 births), these lacerations cause a mortality rate of 17–25% (Ditzenberger 2016). Like cephalohematomas, SGHs are a result of a traumatic birth, especially associated with vacuum-assisted deliveries. Unlike cephalohematomas, an accumulation of emissary vein blood forms in the subgaleal space between the galea aponeurotica and the periosteum of the skull. SGHs are a clinical emergency because this potential space can expand at a rapid rate and can accommodate roughly 260–280 mL of blood which is much more than a newborn’s 90 mL/kg of blood (Reid 2007). Clinically, mass expands rapidly and usually occurs within the first 8 h of life. This laceration can cross all sutures and fontanelles. Important to note that every centimeter gained in head circumference is equivalent to a blood loss of 40 mL (Chaturvedi et al. 2018). Firstly, because the relative blood loss is substantial, intravenous fluids and blood products in addition to intubation and ventilation in severe cases is the primary step in management of hypovolemic shock and resultant respiratory failure (Åberg et al. 2014).
2.4.3 Concussion Concussions are commonly acquired TBI. The pathophysiology of concussions is complex. A concussion is defined as traumatic head injury that results in disruption to normal brain functioning and is related to “neurometabolic dysfunction,” as opposed to discrete structural injury. This type of head trauma is considered as mTBI as the prognosis is generally good and the majority of patients recover within a few weeks (Barkhoudarian et al. 2016). Concussions are often a result of blunt force injury; however, they are also caused by indirect injuries like deceleration injuries. Due to the inconsistency of reporting and a variety of symptomologies, the Center for Disease Control (CDC) estimates an incidence range of 1.4–3.8 million per year (Laker 2011). Of 640,000 TBI-related visits to the emergency department in 2013 in the United States, roughly 70–90% were diagnosed as mTBI (Zhang et al. 2016). The clinical presentation of a concussion varies from patient to patient; however, the symptoms generally fall within one or more of four different areas: emotional lability, cognitive processing and functioning, somatic manifestations, and sleep changes (McCrory et al. 2017). Because no structural changes are appreciated through radiographic studies, the diagnosis of concussion is exclusively clinical. Imaging studies are used to rule out any more serious intracranial processes. There are many clinical assessment scales used to diagnose the severity of concussions. The Post-concussion Symptom Scale (PCSS), Standard Concussion Assessment Tool (SCAT3), Standard Assessment of Concussion (SAC), and Immediate
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Post-Concussion Assessment and Cognitive Testing (ImPACT) are some of the most widely used tools (Zhang et al. 2016; Yeo et al. 2020). Although severity and symptomology can vary widely between patients, the treatment is predominately of supportive care. Patients are put on a personalized stepwise treatment program; however, there is no consistently supported time-frame a given patient should take before returning to daily activities (Ellemberg et al. 2009). Some studies show that individuals can return to baseline functioning within 1 week; however, more studies have shown that complete recovery of symptoms (cognitive functioning, headache, visual changes, and gait stability) may not be achieved until 3 weeks. There is a smaller subset of individuals who progress to develop post-concussive syndrome (PCS). This is diagnosed when patients’ concussive symptoms persist longer than 3 months (Gianoli 2021).
2.4.4 Cerebral Contusion Contusions are bruises that occur on the surface of the brain and consist of different degrees of edema, parenchymal damage, and petechial hemorrhages. These insults occur when a strong enough force results in brain hemispheres separating and compressing forcefully or when the cerebral cortex connects with the inner skull. This can happen as a coup lesion (the brain connects with a skull at the point of impact) or counter-coup lesion (the brain connects with the opposite side of the skull due to whiplash forces) (Cepeda et al. 2019). Cerebral contusions generally occur in the frontal and temporal lobes, most commonly at the vertex of gyri. Severe contusion may result in intra-contusion hemorrhaging causing destruction and necrosis of neuronal tissue (Cepeda et al. 2015, 2019). Like other cerebral manifestations of head trauma, the most common traumatic events to cause contusions are sports, falls, motor vehicle accidents, cycling, domestic violence, child abuse, and blasts. Patients with severe TBI had a contusion rate of 50% (George et al. 2019). Cerebral contusions tend to progress in severity within the first 12 h of injury; however, after this time frame, contusions most likely will stabilize (Kurland et al. 2012).
2.4.5 Traumatic Axonal Injury Of the many different traumatic brain injuries, traumatic axonal injury (TAI) has one of the highest incidence rates. TAI often occurs as a result of high-speed deceleration injuries (MVCs) (Johnson et al. 2013). Axons are long cellular projections from the soma of neurons and are the highway for signal transduction. Due to their length and fragility, they are particularly susceptible to any type of head trauma. TAI is most commonly the result of intracranial shearing forces which disrupt the axonal tract and are frequently accompanied by microhemorrhages. If there are greater than four microhemorrhages found throughout the parenchyma, the injury is considered diffuse axonal injury and has an increased morbidity and mortality
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(Bruggeman et al. 2021). TAI is usually visible on subsequent MRI, showing hemosiderin deposits and axonal damage. CT scans have poor sensitivity for DAI as the microhemorrhages are usually too small. Unless there is a large volume of blood loss, CT scans may come negative (Mesfin et al. 2022).
2.4.6 Skull Fractures Skull fractures are a common comorbidity associated with head trauma; however, the exact incidence rate is sparsely reported. The frontal, sphenoid, ethmoid, two parietal, two temporal, and occipital bones construct the skull. The different bones and their connections vary in strength and size resulting in different types of fractures: linear, depressed, basilar, and penetrating (Ren et al. 2020). Linear fractures commonly occur in the frontal, occipital, and temporoparietal regions, extending through the skull. These insults are only considered clinically significant if they intersect the middle meningeal artery in the middle groove, resulting in extra-axial bleeding in the form of EDH (MacPherson et al. 1990). There is no surgical intervention for linear skull fractures if there is no underlying bleeding. Depressed skull fractures materialize when a substantial blunt force compresses a portion of the calvarium below the adjacent skull. Because the skull and the brain are tightly packed together, this fracture usually results in injury to the underlying parenchyma and the dura mater. This fracture is especially problematic as it increases the risk of infection and mortality (La Russa et al. 2020). A single-center study of 1749 cases showed that depressed fractures had an incidence rate of 0.3% (Hiwatari et al. 2021). Depending on the magnitude of the force necessary for a depression in the skull, roughly 25% of patients experience loss of consciousness (Chesnut 2007). Clinically observed on CT and/or MRI, a depression larger than the width of the skull is significant enough for operative management. A depressed fracture may result in a dural laceration, increasing the risk of infection and seizures; therefore, prophylactic medical treatment is recommended (Bullock et al. 2006). Basilar skull fractures are fractures of one or more bones at the base of the skull. These fractures are products of high-velocity head trauma like motor vehicle accidents (MVCs), motorcycle crashes, and falls. These fractures make up roughly 19–21% of all skull fractures and are commonly associated with hemotympanum, battle sign, raccoon eyes, and cerebrospinal fluid (CSF) rhinorrhea or otorrhea (Potapov et al. 2004). The complication of basilar fractures includes meningitis, hearing loss, cranial nerve palsies, vertigo, cavernous sinus thrombosis, and death. Unless there is intracranial hemorrhaging, these fractures are managed expectantly. CSF leaks are common, presenting in about 45% of all cases. Because of this, prophylactic antibiotics may be considered (Lin and Lin 2013).
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2.4.7 Intracranial Hematomas 2.4.7.1 Epidural Hematoma Epidural hematomas (EDH) are a common result of TBI, occurring in roughly 10% of all cases (Chen et al. 2012). These injuries occur as a result of lacerations of the middle meningeal artery or dural venous sinus. This results in blood accumulation between the dura mater and the internal surface of the skull that does not cross suture lines (Fig. 2.4) (Rosenthal et al. 2017). In relation to the general population trends for head trauma, males and individuals in adolescence and young adulthood are most likely affected by these injuries. The average age of a patient with an EDH is 20–30 years old (Fernández-Abinader et al. 2017). A patient suffering from epidural hematoma usually has a history of a “lucid interval” which describes a period of minutes to hours, post-trauma, where there are seemingly no neurologic sequala. However, the patient begins to deteriorate quickly as the hematoma expands. As the intracranial space is fixed, the accumulation of blood results in increased intracranial pressure and mass effect (Gutowski et al. 2018). If no surgical intervention initiated, depression of central nervous system and death are inevitable. The goal of neurosurgical intervention is to decrease intracranial pressure and stop the bleeding vessel(s). This is often done by burr hole evacuation or larger craniotomies. The most common form of imaging is CT as it is quick and sensitive for EDH. A lens-shaped accumulation of blood on a CT is characteristic of epidural hematomas (Jeong et al. 2016). If these hematomas are recognized early and treated accordingly, patients often have favorable recoveries.
Fig. 2.4 Pathophysiology of traumatic brain hemorrhages following a head trauma. The complex composition of the skull and brain allow for the development of types of intracranial hemorrhages. A SDH (left), most frequently occurring in the elderly population, is the result of a cerebral bridging vein hemorrhage. This leads to blood accumulation between the dura and the arachnoid mater. An EDH (middle), result from a laceration of the middle meningeal artery. These hemorrhages are defined by the accumulation of blood between the internal surface of the calvaria and the dura mater. IPHs (right) result from hemorrhaging of the cerebral vessels and their branches in brain. SDH subdural hematoma, EDH epidural hematoma, IPH intraparenchymal hemorrhages
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2.4.7.2 Subdural Hematoma A subdural hematoma (SDH) is defined as an intracranial hemorrhage that occurs between the dura mater and the arachnoid membrane. Importantly, these hematomas are most commonly an accumulation of venous blood. In acute subdural injuries, bridging veins succumb to traumatic forces to the head. An increased intracranial pressure results in further compartmental tamponade of the bleeding vessel (Fig. 2.4) (Rao et al. 2016). These bleeds are generally found in the frontoparietal region. Roughly 20–30% of subdural hematomas are caused by arterial bleeds. These injuries are found in the temporoparietal region and are more commonly associated with more rapid progression of symptoms (Cheshire et al. 2018). Due to the atrophy of cerebral tissue, subdual hematomas are more common in patients with an average age of 41 years. Subdural hematomas may self-resolve, however, those that do not or present with mass effect will require similar decompressive neurosurgical interventions to epidural hematomas (Van Essen et al. 2019). The diagnosis of SDH is made via CT imaging and presents as a crescent-shaped accumulation of fluid. While many cases can go undetected, many adults and children can live with functional deficits like neurodevelopmental delay (children with acquired subdural hematoma), seizures, and diminished cognitive functioning. 2.4.7.3 Traumatic Subarachnoid Hemorrhage As the name implies, subarachnoid hemorrhages (SAH) occur beneath the arachnoid membrane and above the pia mater (Fig. 2.4). While SAHs occur due to a spontaneous rupture of a saccular aneurysm, these are a common outcome of TBI (Toth and Cerejo 2018). The sight of bleeding is usually seen adjacent to a skull fracture. On CT scans, SAHs are seen within the sulci of the brain and are commonly associated with a “star-sign” pattern and poor outcomes (Hostettler and Werring 2019). Upon diagnosis of SAH, patients are placed in emergency neurosurgical care. External ventricular drain is indicated if the patient is presenting to the hospital with low GCS, signs of increased ICP, and rapid clinical deterioration. In comparison to spontaneous SAHs, post-traumatic SAHs have a relatively good prognosis and an incidence of mortality ranging from 0% to 2.5% (Fragata and Canhão 2019; Rau et al. 2017).
2.5 Biomarkers Although many studies have established and identified potential biomarkers to determine the severity of TBI, none are sufficiently sensitive or specific to be used in the clinical setting. Nevertheless, many serological markers of TBI exist, and research efforts have been aimed to validate and characterize their pathological function. Some of the most promising candidates of TBI biomarkers include S100β, neuron-specific enolase, glial fibrillary acidic protein (GFAP), and Tau (Fig. 2.5) (Kawata et al. 2016). S100β is an intracellular protein that modulates second messenger calcium signaling. Upon brain injury, S100β increases and translocates to the extracellular
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Fig. 2.5 Biomarkers of brain trauma. Head trauma and resultant TBI affect the normal anatomy and physiology of brain cells. These affected cells secrete some specific molecules in response to trauma, which serve as biomarkers of the trauma pathology. For example, injured neurons produce neuron-specific enolase and tau; while glial cells produce a high amount of S100β and GFAP. Researchers use these biomarkers to assess the progression of pathology and efficacy of intervention. (Created with the help of BioRender.com)
matrix. The level of S100β in blood correlates with neuronal damage in the central nervous system (Kawata et al. 2016). S100β serves as a marker for activated astrocytes and increased BBB permeability (Blyth et al. 2009). One study demonstrated that elevated serum levels of S100β strongly correlate with the prognosis of mortality following severe TBI and can serve as acute mortality predictors (Goyal et al. 2013). Another study determined the ranges of serum S100β levels associated with positive or negative outcomes (Glasgow Outcome Score/CT scan) in patients who suffered from a severe TBI. The S100β serum levels falling between 0.3 and 1.6 μg/L resulted in good outcomes; while those between 1.1 and 4.9 μg/L translated into the poor outcomes (Kövesdi et al. 2010). Despite the potential to be a prognostic biomarker for mortality and unfavorable outcomes following TBI, S100β is not the sole reliable marker for TBI. It can be expressed in various other cell types outside of the CNS and can be raised in a variety of pathological conditions such as bone fractures and musculoskeletal injuries (Kawata et al. 2016). Neuron-specific enolase (NSE) is a cytosolic protein involved in axonal transport and can be upregulated after any kind of neuronal damage (Kawata et al. 2016). Many studies have demonstrated that serum NSE levels are increased following moderate to severe TBI and were strongly related to the death or poor outcomes 6 months post-injury (Vos et al. 2004). Concussions or mild TBI’s, however, showed
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no significant fluctuations in NSE serum levels compared to control levels (De Kruijk et al. 2001). Although serum NSE has the potential to become an initial screening tool for poor outcomes TBI, more studies are needed to consider the specificity of NSE since changes in its level are also reported in liver and kidney damage, hypoperfusion, and orthopedic injuries (Kawata et al. 2016). GFAP, an intermediate filament protein that maintains the structural integrity of astrocytes, and as a response to TBI, coordinates the proliferation and activation of astrocytes. Therefore, GFAP levels increase due to mechanical deformations as a result of TBI; translocation into the extracellular space is associated with TBI severity (Kawata et al. 2016). One study showed that serum GFAP levels increase significantly following severe TBI and predict mortality in these patients (Pelinka et al. 2004). Another study investigating the relationship between mild TBI and GFAP levels demonstrated elevated GFAP among patients with abnormal CT scans who suffered from a mild TBI (Metting et al. 2012). Much of the research establishes serum GFAP as a specific marker for astrocytic injury and reduced BBB integrity following TBI. Tau is a microtubule-binding protein that assists axonal trafficking and neuronal signaling; moreover, it plays a crucial role in mediating stretching and retraction against mechanical forces and inertial stress from diffuse brain injuries (Kawata et al. 2016). Tau, therefore, serves as a potential biomarker for diffuse axonal injury following TBI. One study specifically looked at hockey players who suffered from concussion and determined that total Tau serum levels were elevated in these athletes; furthermore, they found that total Tau concentrations were highest immediately after concussion and later decreased during rehabilitation (Shahim et al. 2014). A separate study investigating the effect of repetitive minimal head injuries on Olympic boxers found elevated plasma Tau in the athletes after a fight as compared to controls (Neselius et al. 2013). Collectively, these results suggest that serum Tau levels may be used as a measure of axonal injury following mild TBI’s and repetitive head injuries. However, Tau is an inconsistent and a low-sensitivity biomarker for mild TBI and intracranial injury. However, future studies could address these inconsistencies by enhancing the efficiency of the assay used to determine Tau serum levels (Kawata et al. 2016). Some of the new blood biomarkers for TBI that are currently being studied include, but are not limited to, αII-Spectrin Breakdown Product 150 (SBDP150), αII-Spectrin N-Terminal Fragment (SNTF), Ubiquitin C-terminal hydrolase-L1 (UCH-L1), galectin-3, occludin, matrix metalloproteinases-9, and copeptin. Although more studies are required to validate their specificity and sensitivity, a combination of these biomarkers could help to discriminate between TBI and other injuries that share similar fluctuations in these proteins such as orthopedic injuries (Kawata et al. 2016). UCH-L1 has been studied extensively in the clinical setting of TBI (Diaz-Arrastia et al. 2014; Takala et al. 2016). Recently, a study reported that the serum levels of UCH-L1 can significantly predict death and negative outcomes but are limited in predicting incomplete recovery at 6 months (Korley et al. 2022). Based on the current available data, GFAP seems to perform better in mild to moderate TBI in the first 7 days while UCH-L1 seems to offer better diagnostic accuracy
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in the early post-injury period (Papa et al. 2016). It is questionable that a single biomarker will be specific enough to reflect the breadth of clinical findings in TBI. Further research is necessary to affirm the diagnostic value of all these various biomarkers.
2.6 Future Treatments Therapeutic strategies for TBI aim to prevent secondary injury, enhance brain repair mechanisms, and improve recovery following the injury. Three of these strategies include neuroprotection, neurovascular regeneration, and neurorestoration (Galgano et al. 2017). Neuroprotective intervention has been questionable in terms of therapeutic potential due to inconsistent results found in multiple studies. Some of the approaches involve calcium channel blockers, osmotherapy, amantadine, and erythropoietin (EPO) (Ahluwalia et al. 2021; Jarrahi et al. 2020). Calcium influx is a significant aspect of the cellular damage cascade occurring after TBI and using calcium channel blockers can limit this calcium influx. Various blockers such as nimodipine and ziconitide have been used to treat patients with TBI; although improved outcomes were noted in these patients, significant side effects were observed, and other studies showed contradicting findings with no significant difference between treatment and placebo groups (Galgano et al. 2017). More commonly used in the clinical setting, osmotherapy involves using hyperosmolar agents such as mannitol to control ICP in patients after severe TBI. Mannitol is considered to improve the rheologic properties of blood and to create an osmotic gradient that will help control ICP. Mannitol is effective in decreasing ICP when administered in a dose-dependent manner; however, sodium lactate-based hyperosmolar solution appeared to be more effective and beneficial by improving long-term outcomes in severe TBI patients (Xiong et al. 2009). Amantidine is a dopamine agonist used to treat Parkinson’s disease and acts as an NMDA receptor antagonist. Therefore, it can protect neurons from the excitotoxicity phase of TBI, and studies have shown a moderate improvement in cognitive function and arousal of TBI patients (Sawyer et al. 2008). While EPO is a molecule that has antiexcitotoxic and anti-inflammatory effects, it seems not to improve neurological dysfunction but has an uncertain effect on mortality in patients with moderate to severe TBI (Nichol et al. 2015). Neuronal and vascular regeneration are critical processes that mediate brain recovery after TBI. Using animal models, studies have targeted molecules that may induce or enhance neurogenesis and angiogenesis to promote recovery from TBI. One study found that a Tβ4 active peptide fragment, N-acetyl-seryl-aspartyllysyl-proline (AcSDKP) improved neurovascular regeneration and encouraged the construction of dendritic spines in the brain (Zhang et al. 2017). Moreover, S100β has been found to stimulate neurogenesis through intraventricular administration in the acute or subacute phase of TBI (Galgano et al. 2017). There are two interventions that are currently being studied focusing on neurorestoration following TBI, and they are cell-based therapy and enriched
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environment (EE) intervention. With similar goals of neurovascular regeneration, cell-based therapy involves the use of stem cells to induce the secretion of chemokines and growth factors that augment neurogenesis, angiogenesis, and immunoregulation (Galgano et al. 2017). Although this therapeutic strategy has been deemed safe through various clinical trials, many aspects of the approach such as long-term risks and benefits are still uncertain and require further investigation (Galgano et al. 2017). Enriched environment intervention, on the other hand, focuses on neurorehabilitation aimed at improving emotional well-being by exposing TBI patients to positive environments; studies using animal models of TBI have demonstrated various positive effects of EE in both behavior and neuroanatomy (Galgano et al. 2017). Due to the high incidence of depression in TBI patients, translation of research done on animal models of TBI to humans is crucial to target the neurobehavioral consequences of TBI.
2.7 Conclusion The incidence of traumatic injuries to the head is high and is associated with significant morbidity and mortality. Whether the insulting force is blunt, penetrating, or blast, traumatic brain injury is often the outcome and has a wide variety of clinical presentations that involve lifelong emotional, behavioral, and permanent physical impairments. Understanding the etiology, pathophysiology, and clinical presentation of head trauma allows healthcare workers to develop targeted therapies, screening tests, and enact preventative policies in an effort to abate future incidents. Although there are many gaps in our understanding of TBI, many researchers across the world are striving to understand the nature of head trauma and its neurological sequela. Acknowledgments The authors thank Ms. Anekay Kelly, Medical Illustrator, Department of Neurosurgery for the artwork (Fig. 2.4). The authors also extend their thanks to Biorender for providing online tools for artwork in Figs. 2.1, 2.2, 2.3 and 2.5. Financial support for this project was provided by a grant from the Augusta University Research Institute and by a grant from the National Institutes of Health (R01NS114560). Conflict of Interest Authors have no conflict of interest to declare.
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Current Understanding of DNA Methylation in the Pathogenesis of Neuropathic Pain Hayate Javed, Aishwarya Mary Johnson, and Andleeb Khan
Abstract
Lesion or disease in the somatosensory nervous system is the root cause of neuropathic pain, which has a major negative influence on the quality of life. Injury to peripheral sensory nerves is well documented to change the expression of genes in the neurons and sensory nerves, which has a significant impact on the spinal cord’s synaptic plasticity and the onset and progression of chronic pain. N-methyl-D-aspartate (NMDA) receptors and α2δ1 are examples of pro-nociceptive genes, while potassium channels, opioid, and cannabinoid receptors are examples of anti-nociceptive genes. However, there is still more to learn about epigenetic mechanisms controlling the transcription of these genes. In this chapter, we explored the current research on the role of histone changes and DNA methylation in the development of neuropathic pain. We discussed the importance of neurotransmitter receptors and ion channels expressed transcriptionally under the regulation of these proteins in the dorsal root ganglia following nerve injury, which is frequently utilized in neuropathic pain models. A deeper understanding of the epigenetic reprogramming involved in the transition from acute to chronic pain may lead to the development of innovative neuropathic pain treatments. Keywords
Neuropathic pain · DNA methylation · Histone modification · Nerve injury · Spinal cord · Dorsal root ganglion H. Javed (*) · A. M. Johnson Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates A. Khan Department of Biosciences, Faculty of Science, Integral University, Lucknow, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_3
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3.1 Introduction Neuropathic pain, which persists for months to years, is due to damage to the somatosensory nervous system and remains a major challenge to the clinical neuroscientist for its treatment and management. The most common symptoms of neuropathic pain include allodynia, (increased sensation to innocuous stimulus), hyperalgesia (increased pain perception to harmful stimuli), and spontaneous pain. Various factors are involved in the development of neuropathic pain such as spinal cord injury, diabetic neuropathy, chemotherapy, and herpes zoster virus infection (Postherpetic neuralgia). This devastating disease is quite common in patients who have undergone thoracotomy, mastectomy, limb amputation, or nerve injury- induced trauma (Niraj and Rowbotham 2011; Gottschalk et al. 2006). In addition, neuropathic pain also results from numerous cancerous treatment medications including paclitaxel (Scripture et al. 2006; Sisignano et al. 2014). The chemotherapy- induced spontaneous pain frequently causes the dose of life-saving medication to be reduced or discontinued. Conventional analgesics respond poorly to neuropathic pain, and it is worth identifying the molecular targets of neuropathic pain to find a mechanism-based treatment. Nerve injury-induced neuropathic pain stays longer even after the primary injury is healed. Therefore, it has been assumed that epigenetic processes resulting in changed gene expression are involved. Neurodevelopmental, neurodegenerative disorders, cognition, synaptic plasticity, and embryonic neurogenesis are all impacted by dynamic and reversible epigenetic alterations (Hwang et al. 2017; Qureshi and Mehler 2018). Nucleosomes are the fundamental chromatin- building blocks where DNA and histones interact. Chromatin remodeling is an essential process for regulating how transcription factors physically interact with DNA that is encased in histone proteins (Kouzarides 2007). The tails of histone proteins are positively charged areas that bind to negatively charged DNA. The chromatin structure is affected by histone alterations including methylation, ubiquitination, phosphorylation, and acetylation which frequently occur in various combinations and change the gene transcription in a coordinated manner. Pro-nociceptive genes are essentially required for the persistent stimulation of nociceptive neurons and are highly expressed in neuropathic pain in comparison to antinociceptive genes. In preclinical studies, peripheral nerve injury models are being used to study neuropathic pain, hence, dorsal root ganglion (DRG), where the cell body of the primary sensory neurons is located, is employed in a number of epigenetic studies in this field. In fact, pain-related areas experience alterations in DNA methylation, histone modifications, and non-coding RNAs due to peripheral nerve damage and inflammation (Gazerani 2019; Wang et al. 2014; Mauck et al. 2014; Rahn et al. 2013; Seo et al. 2013). These modifications may be the cause of central neurons’ pain-related genes that have been altered by nerve damage or inflammation. Accumulating evidence suggests that altering epigenetic processes has a role in neuropathic pain development and progression. Lutz et al. (2014) showed that non-coding RNAs containing long non-coding RNAs and microRNAs have a prominent role in pain (Lutz et al. 2014).
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The current book chapter sheds light on the importance of modifications in histone alterations and DNA methylation, primarily in the spinal cord and DRG in neuropathy. In addition, the role of peripheral noxious stimuli in the epigenetic modifications that control genes related to pain is also explored. Further, putative processes by which modifications to histone and methylation of DNA lead to the emergence and persistence of pain are highlighted.
3.2 DNA Methylation The covalent addition of a methyl (CH3) group from the methyl donor S-adenosyl- methionine (SAM) to DNA takes place on cytosines at the 5′ carbon position of the pyrimidine ring (Chiang et al. 1996). The impacted cytosines are primarily found preceding guanosine in purported CpG sites, which tend to group together to form CpG islands, preceding a guanosine, DNA segments of at least 200 base pairs (bp) that are near gene promoters. DNA methyltransferases (DNMTs) are responsible for DNA methylation; in mammals, numerous forms of DNMTs are found and are grouped according to the substrate of DNA and its methylation process. Previously unmethylated CpG sites are recently marked as methylated by DNMT3a, DNMT3b, and De novo DNMTs. DNMTs maintenance like DNMT1 is also required in preserving previously recognized methylation marks (Cheng and Blumenthal 2010). When a cytosine on one strand of DNA is methylated, the corresponding cytosine on the other strand is also methylated by DNMT1, which employs hemimethylated DNA as a substrate. By employing this method, cells make sure that the methylation mark will continue in the event of cell division or DNA damage (Klose and Bird 2006). There are multiple isoforms of de novo DNMTs (i.e., DNMT3a1, DNMT3b1, and DNMT3a2) and three prevalent isoforms of DNMT1 (DNMT1s, DNMT1p, and DNMT1o,). For example, in the case of DNMT3a, the DNMT3a gene locus’s intronic promoter is where the variation originates (Chen et al. 2002). Along with the three canonical DNMTs, there are two non-canonical family members— DNMT2, and DNMT3L—that do not have DNMT catalytic activity. The primary role of DNMT2 is that of a tRNA methyltransferase (Goll et al. 2006), while DNMT3L boosts DNMT3A and DNMT3B’s catalytic activity (Suetake et al. 2004). On a structural level, DNMTs typically have a regulatory domain at the N-terminus and C-terminus and contain a catalytic domain. DNMTs also contain domains that interact with proteins, chromatin, and DNA that control gene transcription. Due to the stability of the underlying covalent bond, DNA methylation was formerly believed to be irreversible and permanent. DNA demethylation, however, can occur passively or actively. Passive methylation of DNA occurs when cell division happens without maintaining DNA methylation. Due to the postmitotic nature of neurons, demethylation of DNA is an active process in these cells. Indeed, numerous studies have demonstrated how dynamic DNA demethylation occurs in the nervous system. The epigenetic erasers DNA damage-inducible (GADD) 45 proteins and growth arrest are connected to DNA demethylation in neurons (Chandramouly 2022) and 10–11 translocations (Tet) family of dioxygenases (Guo et al. 2011). The
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nervous system’s adaptive and maladaptive mechanisms both seem to depend heavily on DNA demethylases (Alaghband et al. 2016; Bayraktar and Kreutz 2018). The methyl-cytosines in methylated DNA either prevent transcription factors from attaching to them due to steric obstruction or because proteins with a methyl-binding domain (MBD) recognize them, which draws proteins with chromatin remodeling, repressor, or transcription factor properties. The epigenetic DNA methylation mark reader that has been prominently investigated and characterized is methyl CpG binding protein-2 (MeCP2), which has been linked to the control of a number of brain processes during both development and adulthood (Gulmez Karaca et al. 2019). Previously, methylation of DNA has been connected to transcriptional repression and tight chromatin. In reality, methylation of cytosines can cause transcription factors to separate from their attachment locations (Watt and Molloy 1988) and make it easier for methyl-CpG-binding proteins (MBPs) to bind, which can draw in complexes of co-repressors (Jones et al. 1998; Nan et al. 1998). Numerous research findings demonstrate that based on the chromosomal position, DNA methylation that can potentially induce gene expression has recently cast doubt on this belief. In fact, it is now evident that DNA methylation does not always imply transcriptional inhibition (Suzuki and Bird 2008). One possibility is that DNA methylation could make the genome more tolerant of responses induced by external stimuli, which is supported by a number of research studies (Oliveira 2016; Baker-Andresen et al. 2013) (Fig. 3.1).
Fig. 3.1 Schematic representation of epigenetic modifications
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3.3 Histone Modification As previously discussed, there are numerous post-transcriptional alterations that N-tails of histone proteins go through. Histone interactions with DNA and additional proteins are affected by post-transcriptional changes, which may help or inhibit transcription. This section will discuss the two most common and well- studied post-transcriptional modifications of histone proteins, i.e., acetylation and methylation. Lysine and arginine residues on histones can be methylated in a number of different states. Arginine can accept one or two methyl groups whereas lysine residues can be mono-, di-, or trimethylated. By altering the chromatin structure and interaction of DNA-histone, various states of methylation/patterns cause the activation or deactivation of transcription of the gene. The most in-depth research has focused on histone 3 on the lysine 4 mark, which is widely abundant at the location where active transcribed genes’ transcription begins. When trimethylated, this site loosens the chromatin and facilitates the recruitment of transcription factors (Santos-Rosa et al. 2002). Contrarily, H3K27 is a marker of gene expression suppression. The family of methyltransferases consists of arginine and lysine methyltransferases based on the residue of their substrate (Allis et al. 2007). Previously, it was believed that histone methylation served as a permanent epigenetic mark, similar to DNA methylation. However, histone demethylation is now understood to be a very dynamic and precise mechanism. According to their substrate and reaction processes, many enzymes have demethylase activity and can be divided into two major families: lysine-specific histone demethylases (LSDs) and Jumonji-C (JMJC) demethylases. Histone proteins’ lysine residues can potentially be acetylated in addition to being methylated. By adding an acetyl group to the positively charged lysine residue, the histone proteins’ electrostatic interaction with the negatively charged DNA is reduced, causing the chromatin structure to relax and, therefore, increasing transcription (Bannister and Kouzarides 2011). Instead, the acetyl group’s removal is typically linked to transcriptional inhibition and a chromatin condition that is more compact. Histone acetyltransferases (HATs) such as p300/ CBP use acetyl CoA as a cofactor to transfer the acetyl group. HATs are sometimes known as K-acetyltransferases (KAT) because they work on a wide variety of proteins, including non-nuclear ones, in addition to histones (Allis et al. 2007). In line with numerous additional families of epigenetic regulators, KATs are widely distributed and classified into subgroups based on their structure and subcellular presence (Nothof et al. 2022). Histone deacetylases (HDACs) remove the acetylation mark. Based on their domains and utilization of cofactors, the 18-member family of HDACs is classified into two main groups: the traditional HDACs are zinc- dependent, which include HDAC classes I, II, and IV; and the class III NAD- dependent sirtuins (SIRT 1–7) (Seto and Yoshida 2014). HDAC1, 2, 3, and 8 belong to class I while class II is additionally classified into IIa (HDAC4, 5, 7, and 9) and IIb (HDAC6 and 10); and HDAC11 categorically belongs to class IV. Class IIa members have a specific nature that affects their function, specifically, the ability to move signal-dependently between the nucleus and cytoplasm (Haberland et al.
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2009; Zhao et al. 2001). Class IIa HDAC subcellular shuttling in pyramidal neurons is regulated by nuclear calcium and the activity of synapse (Chawla et al. 2003; Schlumm et al. 2013). The equilibrium between HAT and HDAC activity controls CNS developmental processes, which either induce or inhibit the transcription of genes (Mehler 2008) and contribute to adaptive mechanisms (Litke et al. 2018; Zhu et al. 2019), aging, and neurodegenerative diseases (Peserico and Simone 2011; Schlüter et al. 2019). Specific domains, including YEATS domains, double plant homeodomain fingers, and bromodomain can be found in readers of acetylated lysine on histone (Khan et al. 2017).
3.4 Histone Acetylation and Deacetylation in Neuropathic Pain The enzymes that acetylate or deacetylate the lysine residues on the N-terminal tail of histones and on the surface of the nucleosome core are known as histone acetyltransferase (HAT) and histone deacetylases (HDACs), respectively (Kuo and Allis 1998). The primary source of the acetyl group used in histone acetylation is acetylcoenzyme A (Kuo and Allis 1998; Gong and Miller 2013). The tightly packed chromatin is frequently relaxed into a more open form via histone acetylation, which encourages the transcription of genes. On the other hand, deacetylation of histone causes the chromatin to become firmly compressed, which silences genes (Kuo and Allis 1998). According to several studies, in neuropathic pain, HDAC inhibitors were found to have an antinociceptive effect. HDAC inhibitor such as sodium butyrate has been shown to reduce TNF-α levels and ameliorate pain hypersensitivity caused by chronic constriction injury (CCI) (Kukkar et al. 2014). However, in CCI-induced neuropathic pain, it is uncertain how HDAC inhibition impacts TNF expression. Thermal and mechanical hyperalgesia was ameliorated in peripheral neuropathy caused by antiretroviral drug (stavudine) and traumatic nerve injury by pretreatment of class I HDAC inhibitors such as MS-275 or MGDC0103 (Denk et al. 2013). This analgesic effect of class I HDAC inhibitors could be due to a rise in the spinal cord’s global H3K9ac but not in DRG, implying that a possible mechanism has a significant impact on CNS (Denk et al. 2013). It is worth mentioning that a neuropathic pain model has revealed acetylation alterations at the promoters of genes related to pain, including Nav1.8, Kv4.3, mu opioid receptor, and brain-derived neurotrophic factor (BDNF) in neurons of DRG (Matsushita et al. 2013; Uchida et al. 2010a, b). Diminished H3 and H4 histone acetylation caused by nerve injury at Kv4.3, Nav1.8 promoter’s regions and mu receptor inhibits their expression in DRG neurons and could be responsible for the negative neuropathic pain symptoms (Uchida et al. 2010a, b), while nerve damage-induced increase in the acetylation of histone H3
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and H4 at CdK5 promoter’s regions in the spinal cord and BDNF promoter regions in DRG enhance the production of CdK5 and BDNF, respectively, which may result in neuropathic pain condition (Uchida et al. 2013; Li et al. 2014). According to findings from other studies HAT inhibitors had antinociceptive effect on neuropathic pain. Anacardic acid an inhibitor of HAT decreased the neuropathic pain caused by spinal nerve ligation (SNL) by diminishing histone H3 hyperacetylation in the promoter region of chemokine CC motif receptor 2 (CXCR2) and macrophage inflammatory protein 2 (MIP-2). This was done by preventing the up-regulation of CXCR2 and MIP-2 brought on by SNL in the injured sciatic nerve (Kiguchi et al. 2012, 2013). In the spinal cord, CCI upregulated the level of p300 protein which binds to HAT E1A (Zhu et al. 2012, 2013). Intrathecal injection of an inhibitor of p300 HAT and p300 shRNA diminished the level of cyclooxygenase-2 (COX-2) in the spinal cord and reversed thermal and mechanical hyperalgesia caused by CCI (Zhu et al. 2012, 2013). Resveratrol, a class III HDAC, an activator of Sirt1, reliably reduced the effects of CCI-induced thermal and mechanical hypersensitivity and prevented the acetylation of histone H3 in the spinal cord as well as reversed the decline in spinal Sirt1 (Yin et al. 2013). Other persistent pain syndromes have also been linked to the analgesic impact of HAT inhibition. Anacardic acid, a HAT inhibitor, was administered intraperitoneally in an incision model to lessen incision-induced pain hypersensitivity (Sun et al. 2013a, b). Suberoylanilide hydroxamic acid, an HDAC inhibitor, increased mechanical hypersensitivity following incision (Sun et al. 2013a, b). Given that the mechanisms of opioid tolerance, neuropathic pain, and hyperalgesia caused by drugs overlap similar biochemical pathways (Mayer et al. 1999), the finding demonstrates that histone alteration results in opioid tolerance and hypersensitivity, which are brought on by the opioid. In fact, consecutive 4 days of injections of curcumin (HAT inhibitor) together with morphine prevented the emergence of morphine-induced physical dependence and tolerance as well as mechanical and thermal hypersensitivity (Liang et al. 2013). Contrarily, HDAC inhibitor, SAHA, enhanced these responses (Liang et al. 2013). It has been demonstrated that resveratrol inhibits the growth of morphine analgesic tolerance, reverses the effects of morphine on spinal Sirt1, and reduces the effects of morphine on spinal histone H3 acetylation (He et al. 2014). It is worth mentioning that baicalin, a flavonoid molecule derived from Huang Qin, reduced HDAC1 expression and stopped the spinal acetylation of histone-H3, which in turn reduced neuropathic pain caused by SNL (Cherng et al. 2014). Based on the above-described observations, it is yet unknown how HDACs and HATs are related to neuropathic pain. It is unknown if acetylation and deacetylation of histone have a significant impact on neuropathic pain (Fig. 3.2).
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Fig. 3.2 Nerve injury-induced epigenetic modifications and transcriptional alterations in genes associated with neuropathic pain
3.5 DNA Methylation in Neuropathic Pain Neuropathic pain models showed alterations in the methylation of comprehensive DNA in the spinal cord and DRGs weeks following injury, supporting the notion that methylation may have a significant impact on persistent pain (Garriga et al. 2018; Wang et al. 2011). Numerous research findings reported that an increase in methylation in promoter sites of certain gene promoters is related to chronic pain, apart from DNA’s overall degree of methylation. For instance, potassium voltage- gated channel (Kcna2) and mu 76 opioid receptor (MOR) gene promoter methylation levels were found to be higher in neuropathic pain models, and these genes’ decreased protein levels were consistent with respect to how DNA methylation inhibits the expression of certain genes (Shao et al. 2017; Sun et al. 2017, 2019). Epigenetic downregulation of MOR may explain why opioid analgesic effects reduce neuropathic pain. Kcna2 expression is thought to be a major determinant of neuronal excitability in DRG (Chien et al. 2007; Fan et al. 2014). In neuropathic pain, several promoter areas were found hypomethylated which indicates that changes in DNA methylation pattern are not entirely unidirectional in favor of increase. The neuropathic pain model based on spinal nerve ligation (SNL) showed that G protein-coupled receptor 151 (GPR151) and chemokine receptor 3 (CXCR3) gene’s promoter were less methylated than previously observed. A significant impact of CXCR3 has been observed on the pathophysiology of diseases caused by
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inflammation and is connected to pain modulation in the spinal cord and DRG (Aloyouny et al. 2020). In neuropathic pain, DRG hyperexcitability has been linked to GPR151 (Xia et al. 2021). Chronic pain of different conditions, such as visceral and inflammatory pain, was associated with distinct states of methylation, demonstrating that methylation modifications are not unique to neuropathic pain (Qi et al. 2013; Yuan et al. 2020; Hong et al. 2015). One of the most well-studied and often used models of chronic inflammatory pain is induced by the injection of complete Freund’s adjuvant (CFA) in the skin of the hind paws of rats or mice. The injection of CFA leads to demethylation in the promotor regions of genes encoding the nerve growth factor (Yuan et al. 2020) or enzyme cystathionine-synthase (Qi et al. 2013). The simultaneous induction or suppression of DNMT expression serves as a mechanism for implementing the identified alterations in DNA methylation. DNMTs expression pattern changes in many pain conditions, in DRG as well as in spinal cord and can be bidirectional similar to what has been seen for the promoters of specific genes. In SNL and CCI rodent models of neuropathic pain, DNMT3a has been shown to be increased (Shao et al. 2017; Saunders et al. 2018; Sun et al. 2017; Zhao et al. 2017; Xu et al. 2017; Liu et al. 2020). These reports did not distinguish between DNMT3a2 and DNMT3a1 as DNMT3a isoforms. However, the expression and activity patterns of the two isoforms in other parts of the nervous system are very different. While DNMT3a1 levels remain stable, synaptic activity regulates and induces the production of DNMT3a2 in the mouse hippocampus (Oliveira et al. 2012). Intraplantar injection of CFA causes inflammatory pain in rodents and it was found that CFA treatment primarily activated DNMT3a2 in the dorsal horn of the spinal cord of mice whereas DNMT3a1 was seen unaffected (Oliveira et al. 2012). The hypomethylation status of multiple genes in both inflammatory and neuropathic pain is believed to be caused by the decrease in DNMT3b, and this decrease occurs in the opposite manner from that described for DNMT3a in the majority of studies (Jiang et al. 2017, 2018; Yuan et al. 2020). The role of DNA methylation in chronic pain is further supported by evidence pertaining to readers of this epigenetic mark. Phosphorylation and subsequent inactivation of MeCP2 were observed in the spinal cord of rats following intraplantar injection of CFA which causes inflammatory pain (Géranton et al. 2007). Additionally, animals lacking MBD1 displayed changes in pain hypersensitivity (Mo et al. 2018).
3.6 Conclusion and Future Perspectives According to the findings outlined above, DNA methylation and histone modifications in the DRG and spinal cord are linked to pain. The conclusion is based on behavioral observations made after the injection of a pharmacological inhibitor. The specificity and selectivity of these inhibitors for the respective epigenetic enzymes vary. They may also have impacts via non-epigenetic processes, which could have negative effects. For instance, many cytoplasmic targets can be acetylated and deacetylated by HATs and HDACs since they are not histone specific. Due to these
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considerations, it is important to read recent data carefully when it suggests that a specific epigenetic enzyme is responsible for chronic/neuropathic pain. As a result, it will be necessary to create pharmacological inhibitors of isoform- or subtype- specific epigenetic enzymes as well as to apply targeted genetic suppression of these enzymes. Furthermore, research is still needed to determine whether noxious stimuli can trigger these epigenetic enzymes that are experienced peripherally and how this activation affects neuropathic pain. Future research may provide much more information on the role of histone modification and DNA methylation in chronic pain. Given that neuropathic pain remains a difficult condition to treat and that the significance of the epigenetic mechanisms underlying this life-threatening illness is becoming increasingly clear. Conflict of Interest The authors declare no conflict of interest.
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4
Decoding Dystrophin Gene Mutations: Unraveling the Mysteries of Muscular Dystrophy Zeenat Mirza and Sajjad Karim
Abstract
Muscular dystrophies are a group of human monogenic disorders causing muscle weaknesses and affecting mobility. Mutations in different genes cause different types including Duchenne, Becker, congenital, Emery–Dreifuss, oculopharyngeal, facioscapulohumeral, myotonic, and limb-girdle muscular dystrophy. Dystrophin gene mutation causes dystrophinopathy, including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy (DCM), and together these account for approximately 50% of all muscular dystrophies. Dystrophin, the largest known gene in humans is located in chromosome Xp21, spans approximately 2.4 Mb and constitutes 0.08% of the genome. Dystrophinopathy, mainly affecting males with an incidence rate of 1/3500, is characterized by progressive muscle weakness and cardiomyopathy. Initially, weakness emerges in the hips and upper leg muscles around the age of 4, but it can extend to involve the heart, gastrointestinal tract, and respiratory muscles later in the disease course, and the weakness intensifies with time. Although the severity and survival time might vary for DMD, BMD, and DCM, dystrophinopathy has no cure except for the recent gene-therapy Z. Mirza King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia S. Karim (*) Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_4
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approach. Strategies and the potential of innovative therapeutic approaches for DMD have been discussed. Keywords
Muscular dystrophy · CNS · Dystrophin
4.1 Introduction Muscular dystrophies (MD) are inherited myogenic disorders characterized by progressive muscle weakness and wasting. Its onset varies; early-onset muscular dystrophies are more severe and cause loss of muscle function, walking inability, and cardiac and respiratory problems that might lead to death, while late-onset forms are mild with weakness in different skeletal and smooth muscles. The first-time muscular dystrophy was described by Sir Charles Bell in 1830 in boys as additional symptoms of tuberculosis causing progressive muscle weakness/damage. Duchenne muscular dystrophy was first termed and described by Dr. Guillaume Duchenne in the 1860s, and dystrophin (gene symbol DMD) was discovered by Dr. Louis Kunkel in 1987. Dystrophin is the largest human coding gene (2.24 Mb, roughly 0.08% of the whole genome) located at chromosome Xp21 in minus orientation (Koenig et al. 1987). It comprises 79 exons and takes over 16 h to be transcribed and codes for a 427-kDa cytoskeletal protein, a member of the β-spectrin/α-actinin protein family (Ferlini et al. 2013). Quality (partially functional) and quantity (loss or gain) of dystrophin protein in muscle cells determine their strength, fragility, and injury. It is mainly expressed in skeletal, cardiac, and smooth muscles and helps in muscular movement and heart pump by contracting and relaxing muscles. However, its limited presence has also been reported in nerve cells in the brain, especially in synapses or the retina, but the function is not completely characterized yet. Multiple genes encoding for the extracellular matrix, sarcomere, plasma, and nuclear membrane proteins are associated with nine major groups of muscular dystrophies. These groups include Duchenne MD, Becker MD, myotonic dystrophy, limb-girdle MD, facioscapulohumeral MD, congenital MD, distal MD, oculopharyngeal MD, and Emery–Dreifuss MD. Each type of MD affects specific muscles with variable distribution, severity, age of onset, and inheritance pattern, and affects muscle groups (skeletal, smooth) and organs (limbs, gastrointestinal system, respiratory tract, heart, eye, face, endocrine glands, spine, and brain) (Emery 2002; McNally and Pytel 2007; Flanigan 2014; Zhang et al. 2021). All forms of MD grow worse with age and symptoms can include progressive muscle weakness and wasting, chest infections, cardiomyopathy, facial weakness, ankle swelling, joint stiffness, cataract, drooping of the eyelids, sleeping disorders, shortness of breath, swallowing difficulties, digestive problem, intellectual disability, faints, collapses, cardiac arrest, and death. Diagnosis of MD types is recommended clinically but confirmed by genetic testing or by quantifying protein products. DMD, DMPK,
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ZNF9, DUX4, LAMA2, PABPN1, EMD, etc. mutations can be detected by a genetic test. The major types of dystrophies are briefly discussed below. 1. Duchenne MD (DMD) is the most frequently inherited muscular disorder in children accounting for approximately 40% of all muscular dystrophies, caused by the loss of the dystrophin gene, and exhibits severe symptoms with the patient not surviving beyond 25 years. Because dystrophin is present on the X-chromosome and Duchenne MD follows the X-linked recessive mode of inheritance, boys are primarily affected, and girls are carriers with minor or no symptoms. 2. Becker MD (BMD) has similar but milder symptoms and has late-onset than DMD. BMD patients have a partial loss or insufficient dystrophin protein leading to variable clinical outcomes appearing around 10–20 years and patients may survive till their 50s. 3. Myotonic dystrophy is characterized by hypotonia (prolonged muscle contractions), weakness of muscle, cataracts in the eye, slurred speech, cardiac conduction defects, and abnormalities in the endocrine and CNS. Myotonic dystrophy type 1 and type 2 are caused by a mutation in DMPK and ZNF9 genes, respectively. 4. Limb-girdle MD has 33 forms, and mutations in the following genes (CAPN3, SGCA, DYSF, ANO5, SGCB, SGCG, SGCD, FKRP, TTN, TCAP, TRIM32, POMT1, FKTN, POMT2, GMPPB, ISPD, POMGNT1, DAG1, PLEC1, TRAPPC11, POGLUT1, collagen VI, LAMA2, POMGNT2, BVES, POPDC3, and JAG2) produce abnormal proteins affecting muscle function that is associated with different forms of LGMD. 5. Facioscapulohumeral MD (FSHD) is an inherited neuromuscular dystrophy, prominently affecting the facial, shoulder and upper arms muscles, and rarely hearing loss, caused by reduction/contraction of DUX4 gene within D4Z4 repeat units. 6. Congenital MD (CMD) has 30 different known types of autosomal recessive disorders affecting central nervous system atrophy, cerebellar atrophy, spinal rigidity, eye muscles, severe intellectual disability, joint hyperlaxity, epidermolysis bullosa, hypertrophy, respiratory failure, myasthenic syndrome, Walker– Warburg syndrome, Fukuyama CMD, Merosin-deficient CMD, Santavuori muscle–eye–brain disease, and Ullrich CMD. Mutation in the following genes LAMA2, CHKB, FKRP, COLGA1, COL6A2/3, B3GNT1, POMT2, ISPD, GTDC2, TMEM5, B3GALNT2, SGK196, POMGnT1, LMNA, FKTN, SBP2, LARGE, PLEC, ITGA9, ITGB9, and SEPN1 are known to cause CMD to both boys and girls. 7. Distal MD primarily affects the distal muscles of hands and feet and is less severe but can adversely affect the heart and respiratory muscles as well. Different types of distal MD such as Miyoshi, Finnish, Nonaka, and Gowers– Laing distal myopathy, Welander and distal myopathy with vocal cords, and pharyngeal weakness are caused by mutations in DYSF, TTN, GNE, and MYH7 genes and abnormalities in chromosomes 2 and 5, respectively.
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Fig. 4.1 Domain structure of the dystrophin protein showing its various domains from N to C terminal. The four “hinge” regions are denoted by H1–H4
Fig. 4.2 Three-dimensional structure of DMD protein. (a) Amino-terminal actin-binding domain, the four chains highlighted in different colors (PDB: 1DXX), (b) structure of a dystrophin WW domain fragment complexed with a β-dystroglycan peptide (PDB: 1EG3). (c) Amino-terminal spectrin repeat 1 of dystrophin (PDB: 3UUN)
8. Oculopharyngeal MD (OPMD) causes the weakness of extraocular (upper eyelids) and pharynx (throat) muscles and patients have ptosis (drooping of the eyelids), ophthalmoplegia (problem in eyes movement), and dysphagia (difficulty in swallowing). Mutation in the PABPN1 gene is known to cause OPMD. 9. Emery–Dreifuss MD is a degenerative myopathy that weakens muscles without affecting the nervous system. EMD, LMNA, SYNE1, SYNE2, TMEM43, and FHL1 genes are found to cause different types of EDMDs.
4.2 Cellular Roles of Dystrophin The dystrophin protein is the main component of skeletal muscle cells and has four distinct functional domains with a rod shape of approximately 150 nm long. The DMD protein has an amino-terminal actin-binding domain that binds to F-actin, a central rod domain comprising of spectrin-like repeats, a cysteine-rich domain, and
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a carboxy-terminal domain that binds to the dystrophin-associated glycoprotein (DAG) complex in the membrane (Fig. 4.1). Figure 4.2a crystal structure is determined at a resolution of 2.6 Å and shows an antiparallel dimer of two actin-binding domains, each containing two α-helical globular folds (calponin homology domains, CH1 and CH2) linked by a central α-helix. Figure 4.2b shows the partial structure of a dystrophin WW domain complexed with a β-dystroglycan peptide. Figure 4.2c exhibits the three-helix bundle fold of the N-terminus first spectrin repeat. Dystrophin’s four domains interact extracellularly with α-dystroglycan and interact with dystroglycan, sarcospan, and sarcoglycan in the membranes, and with syntrophin, dystrobrevin, and nNOS in the cytoplasm to form the dystrophin complex (Gao and McNally 2015). Dystrophin serves as a link between the actin-based cytoskeleton of the muscle cell through the plasma membrane and the extracellular matrix. Basically, dystrophin–glycoprotein complex acts as an anchor by joining each muscle cell’s structural framework “cytoskeleton actin” to the lattice of proteins and other extracellular molecules via the sarcolemmal dystrophin-associated glycoprotein complex (Zhou et al. 2017). Dystrophin along with other proteins forms a complex to strengthen muscle fibers and protect them from injury. It is also believed that the dystrophin complex mediates cellular signaling such as mechanical force transmission and cell adhesion. Muscles are made up of numerous muscle fiber cells bound together by connective tissue during development. Muscle activation is regulated by neuro-signal causing the release of acetylcholine at the neuromuscular junction responsible for triggering a series of events for muscles to contract or relax. For smooth contraction and relaxation of muscle fibers, the dystrophin–glycoprotein complex proteins at the muscle fiber membrane provide protection from damage. Mutation in dystrophin causes damage to muscle fibers membrane causing the leakage of creatine kinase, a protein required to produce energy for contractions, and excessive calcium gets inside the membrane, further increasing the damage that leads to progressive muscle degeneration of tissues/ organs. Gradually it affects the integrity of muscle fibers, such as fiber branching and splitting, fiber death, fiber cell phagocytosis, shortening of tendons and muscles, and replacement of muscle by fat that finally causes loss of muscle strength and tendon reflexes and ultimately muscular dystrophy (MD). Pathogenic mutations in dystrophin result in Duchenne or Becker muscular dystrophy.
4.3 Dystrophin-Associated Disease Genetic variations in the dystrophin gene cause tissue-specific dystrophinopathies, progressive degenerative muscle disorders, like DMD, BMD, X-linked dilated cardiomyopathy (XL-DCM), and carrier dystrophinopathy (CD). However, dystrophin’s expression in the brain, retina, and gastrointestinal muscles also causes disease. It follows an X-linked recessive mode of inheritance, affecting 1 in 3500 males in early childhood with proximal weakness at 3–5 years that extends to distal weakness leading to wheelchair-bound around 12 years, and respiratory
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insufficiency or cardiac failure might occur after 15 years (Muntoni et al. 2003; Gao and McNally 2015). Deletion, duplication, and small/point mutation in the dystrophin gene cause diseases with heterogeneous clinical phenotypes and genetic characteristics. Even though dystrophin gene mutations are responsible for both muscular dystrophies, DMD and BMD, still the clinical phenotypes and therapies are unlike (Zhou et al. 2017). Duchenne muscular dystrophy (DMD): It affects about 1/5000 males and manifests around 2–3 years of age with weakness in proximal lower limbs muscles initially where kids do toe and side-by-side walking with frequent falls, face difficulty in running, jumping, climbing, etc., and suffer from lordosis (inward curve of lumber spine) (Mendell et al. 2012; Long et al. 2018). The development of weakness is constant, and nearly all infants acquire limb flexion contractures and scoliosis. Firm pseudohypertrophy occurs (fatty and fibrous substitution of enlarged muscles, most prominently in the calves). Generally, patients require a wheelchair by the age of 12 and perish of respiratory complications by the age of 20. Becker muscular dystrophy (BMD): The BMD symptoms are similar to DMD in the pattern of muscle wasting and weakness, but mild with a late onset of ~12 years; followed by loss of ambulation and death in the fifth decade onward. Clinical features of BMD include exertional cramping and swelling in thigh muscles, exercise intolerance with myalgia (pain all across the body), myoglobinuria (red-brown urine with excessively degraded muscular myoglobin), and high serum levels of creatine kinase (Doriguzzi et al. 1993; Fujii et al. 2009). X-linked dilated cardiomyopathy (XLDCM): XLDCM is a rare dystrophinopathy causing fibrosis and atrophy of cardiac muscles with normal skeletal muscles. Arrhythmia (irregular heartbeat), sinus tachycardia (fast heartbeat), and conduction abnormalities are common cardiac involvement causing abnormal blood circulation in DCM patients. Such symptoms start by age 6, get complicated over time, and affect all patients by age 20. However, later in adverse conditions fibrosis appears initially in the myocardium that becomes progressive fibrosis with time, causing left ventricular dysfunction and leading to heart failure (Kamdar and Garry 2016). Cardiomyopathy was also reported in DMD and BMD patients. Implantable cardioverter-defibrillators are advised for patients with a left ventricular ejection fraction C and hsa-pre-mir-146a rs2910164 G>C” were sequenced genotypically in high-risk Chinese patients of schizophrenia (268) and controls (232). But neither of these two SNPs nor schizophrenia showed a statistically significant relationship (Zou et al. 2012). SNP rs7289941 showed a negative association as well (Zhang et al. 2012). Current investigation showed that the two-stage GWAS of schizophrenia is involved in controls’ study and cases (4384 and 5770 respectively), as well as independent replications of 13 SNPs apart from Han Chinese ancestry controls and schizophrenia cases (7043 and 4339 respectively). Authors observed that 10q24.32 (rs10883765, in an intron of ARL3, and rs10883795, in an intron of AS3MT), 2p16.1 (rs1051061, in an exon of VRK2), and 6p22.1 (rs115070292, in an intron of GABBR1) are three positions which are remarkably related with schizophrenia. Cell adhesion molecules, myelination pathways, and GABAergic as well as dopaminergic transmission are all known to be mediated by these three positions (Yu et al. 2017).
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Correct miRNA processing is controlled by the hairpin structure, and miRNA/ mRNA interaction is regulated by the 3′UTR of mRNA. SNPs in these areas may increase the risk of sickness. A polymorphism was detected in the region of the miR-130b gene that is 5′-upstream of the vulnerability loci (22q11) for schizophrenia in the Russian population, which includes DNA fragments for putative transcription factors in that region. Nevertheless, a statistically relevant link between schizophrenia and miR-130b variants could not be established through genetic research (Burmistrova et al. 2007). Another author reported a set of human SNPs in binding sites of anticipated miRNA-mRNA- to GWAS for schizophrenia and recognized 7-miRNA which are associated with SNPs (Liu et al. 2012). A current investigation showed that the Gibbs-free energy of miRNA binding in silico was evaluated for 803 SNPs from the 3′UTR of 425 schizophrenia-related genes. The understudied SNP (rs3219151 of GABRA6) has been found to be ominously linked to a decreased prevalence of schizophrenia. The vulnerability of schizophrenia is increased due to both SNP and rs10759 (RGS4), which could be obstructed as a result of miR-124’s, and has the ability to bind to RGS4 (Gong et al. 2013). In the Chinese Han population, the widely held SNP analysis was done. In schizophrenia patients, a large number of samples of genetically different north Indian cohorts were analyzed in connection with MiRSNPs (John et al. 2016) (1017 cases and 1073 controls). The authors found that 12 and 5 SNPs were related with schizophrenia and tardive dyskinesia genes, respectively. A current genome-wide study of Canadian patients revealed that the presence of CNVs in abundant quantity overlaps miRNAs by removing the 22q11.2 CNVs, which is a major risk factor for schizophrenia (Warnica et al. 2015). The 25 miRNAs with CNV overlaps that were expected targets seemed to be engaged in neurodevelopmental processes (Warnica et al. 2015). These investigations indicated that the role of miRNAs could have a vital part in the neuropsychiatric illness by targeting genes associated with schizophrenia. Recently a polymorphism (rs1625579) identified in an intron of the primary miR-137 transcript has been receiving a lot of interest and was determined to be substantially linked with schizophrenia in GWAS (p = 1.6 × 1011). Multiple studies have verified the link between schizophrenia samples and miR-137 polymorphisms in the Scottish (Whalley et al. 2012), Canadian (Lett et al. 2013), Australian (Green et al. 2013), Chinese Han, and Scottish population (Guan et al. 2014; Ma et al. 2014). Nevertheless, numerous case–control investigations have shown negative correlation results (Egawa et al. 2013; Yuan et al. 2015). In the Psychiatric GWAS Consortium investigation of schizophrenia, four putative target genes (C10orf26, CACNA1C, TCF4, and CSMD1) were also found to have substantial genome-wide correlations with schizophrenia. The connections between these four target genes and miR-137 were confirmed using the luciferase report assay (Kwon et al. 2013), also ZNF804A (Kim et al. 2012) and CALN1 showed comparable effects. Multiple target genes such as HTR2C, ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, and NRG2 were found using bioinformatics techniques. These genes have been linked to synaptic long-term potentiation, which may be the possible mechanism affecting learning and memory function in people with
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schizophrenia (Wright et al. 2013). Functional magnetic resonance imaging (MRI) scans revealed that the rs1627759 TT (miR-137 locus) is related to hyperactivity of DLPFC, that is used to determine the inefficiency of the brain (Potkin et al. 2014). Another report revealed about the association between the expression of miR-137 and genotypes of rs1625579 (Guella et al. 2013). In comparison to the TG and GG participants in the control group, the homozygous TT individuals had reduced miR-137 levels of expression. The miR-137 target gene TCF4 was more prevalent in TT patients, whereas miR-137 levels were less (Guella et al. 2013). Another report showed that the expression of the miR-137 variants in SH-SY5Y dopaminergic cell line decreased the production of mature miR-137 and resulted in the dysregulation of sets of genes responsible for the transfer of neural signals and synapse formation (Strazisar et al. 2015). Nevertheless, the authors also discovered that miR-137 function was increased while bearing variant alleles. Researchers observed that higher levels of miR-137 expression resulted in decreased expression of presynaptic target genes such as complexin-1 (Cplx1), synaptotagmin-1 (Syt1), and Nsf, which inhibited the release of vesicles. An increase in the function of miR-137 resulted in the alteration of synaptic vesicle pool distribution, mossy fiber continuing potentiation was hindered in vivo, and memory and learning functions that depend on the hippocampus were affected (Siegert et al. 2015). Therefore, these studies showed that a change in miR-137 might be crucial for the pathogenesis of schizophrenia.
6.4 Mechanisms for miRNA Dysregulation in Schizophrenia In a similar way to that of mRNA, chromatin structure and transcription factors govern the expression of almost miRNA genes from polymerase II promoters. Generally, these transcripts are produced from either the introns of protein-coding mRNA or non-coding mRNAs. As a result, just as with every gene, the level of transcription will change depending on the current regulatory environment and epigenetic state. The stability of repetitive sequence motifs in the enhancers and activator components of miRNA would also affect the transcription of such molecules. Following transcription, the primary hairpin that depends upon identical sequences which regulate the machinery of miRNA biogenesis will also be crucial for their processing into precursor and mature miRNA (Catalanotto et al. 2016). All these miRNA gene components are changeable and can cause heritable alterations in the genome with functional implications for disorders including schizophrenia. The previous investigation initially established the relationship between schizophrenia miRNA polymorphisms using 28 brains expressing miRNA in a Scandinavian population (Danish, Swedish, and Norwegian patients n = 420/163/257, controls n = 1006, 177, and 293). Nevertheless, the functional relevance of these polymorphisms was not established. Remarkably, two miRSNPs, located in miR-198 (Norwegian sample p = 0.038) and miR-206 (Danish sample p = 0.0021), were reported to be related to schizophrenia (Hansen et al. 2007). Another study reported on a male Caucasian population (n = 193 cases and
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191 controls) and investigated miR-502 and miR-510 that are linked to schizophrenia. In vitro, the production of precursor and mature miR-502/510 transcripts was lowered because of this function of specific polymorphisms, which were also linked to decreased miRNA processing. It is believed that the SNP’s detrimental effects on Drosha breakage are the cause of the decreased processing, in particular, in the case of miR-502 (Katsel et al. 2005). Additionally, authors studied the possibility that exceptionally rare variations in X-linked miRNAs could enhance the development of schizophrenia risk since they are associated with decreased fertility and the generation eradication of increased X-linked abnormalities (Rees et al. 2011). In three men with schizophrenia, they reported eight infrequent types in the miRNA precursors such as “pre-miR-505; pre-miR-502; pre-miR-18b,” and five in the mature transcripts including “miR-188-3p; miR-325-3p; miR-509-3p; miR-510-3p; miR-660; let-7f-2” (Prabakaran et al. 2004). Pre-mir-30e was found to have a novel variation in a Chinese case–control study. A poor association between genes for schizophrenia susceptibility was shown by mature miR-24, MAPK14, and miR-30e when coupled with SNPs (Mellios et al. 2008; Xu et al. 2010). Currently, it is demonstrated that the complexion 2 gene (CPLX23′UTR)’s SNP, which contains the T allele, increases the affinity with which miR-498 attaches to the target protein, presumably having a genotype-dependent effect on the gene’s expression. MIR137 is one of the most intriguing miRNA genes linked with schizophrenia. The most significant novel link with schizophrenia was found in a current GWAS, which revealed the rs1625579 SNP downstream of miR-137 (Guella et al. 2013; Liu et al. 2018). Despite the gene for this long non-coding RNA transcript (AK094607) produces the main transcript for miR-137 which is almost 100 kb. Because it appears inside the intron of the parent transcript, the efficacy of this polymorphism in relation to miR-137 production is not clear properly, and it could act as an indicator SNP for other, closer-to-the-miRNA hairpin variants that are more therapeutically significant. Previous findings suggest that further investigation is required to define the character of this mutation or linked polymorphisms in relation to miR-137 (Tamminga and Holcomb 2005). Although this is the first study to link miR-137 with schizophrenia, it has been demonstrated that miRNA modulates neuronal maturation and adult neurogenesis that is found in the brain (Smrt et al. 2010; Szulwach et al. 2010), the processes whereby difference may be involved in schizophrenia’s impaired brain activity. Remarkably, a multitude of protein-coding genes, for instance, Sushi multiple domains 1 (CSMD1), C10orf26, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C), CUB as well as transcription factor 4 (TCF4) are significantly anticipated targets of miR-137. Therefore, it is likely that this gene might transmit vulnerability that is carried out by several genes via a disruption in miRNA activity (Perkins et al. 2007) as in Fig. 6.2.
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Fig. 6.2 MiRNA biogenesis mechanism and function. Adapted from Tufekci et al. (2014)
6.5 Alterations in miRNA Biogenesis Although miRNA is modulated, it is also modified in the miRNA through biogenesis mechanism, in addition to, sensitivity to mutation at cis position with different genes (Han et al. 2006; Thomson et al. 2006). These outcomes revealed that the pathophysiology of neuropsychiatric and neurological disorders including schizophrenia is associated with abnormalities in the maturation and mechanism of cellular miRNA. In addition, it was observed that a variation in copy number as well as polymorphisms of gene in miRNA occurs in the process of biogenesis and overpresentation in schizophrenia and is associated with neurobehavioral diseases (Blow et al. 2006). The 22q11.2 microdeletion syndromes are also called DiGeorge or Velo-Cardio-Facial Syndrome (VCFS) and are the most well studied of such connections.
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Numerous symptoms, such as cognitive impairments and neurobehavioral issues, are present in such disorders. One of the biggest causes for schizophrenia progression is due to genetically identical or having two parents with this disorder. However, early adulthood and adolescence will experience schizophrenia with the deletion which is nearly 30% of children (Bassett et al. 2003). Additionally, it has been shown that 22q11.2 microdeletions, which incorporate around 2% of sporadic schizophrenia cases, are the cause of new instances of schizophrenia in the community (Xu et al. 2008b). The most frequent loss is 3 Mb in size, while a nested 1.5 Mb deletion contains several schizophrenia-related genes. This area is preserved within the syntenic region of mouse chromosome 16 and comprises almost all human orthologues. Stark et al. (2008) created a mouse model with the human 1.5 Mb microdeletion. Therefore, the Dgcr8 gene (a component of the microprocessor complex in the miRNA biogenesis pathway) was hemizygously deleted, and 25 brain-related miRNAs were downregulated. Researchers claim that the haploinsufficiency of the Dgcr8 gene causes aberrant miRNA synthesis, which in turn causes behavioral and neurological impairments linked to the 22q11.2 microdeletion. Two other research teams have recently looked at Dgcr8+/ knockout animal models to study the impact of Dgcr8 loss on miRNA expression and neuronal shape (Stark et al. 2008). Schofield et al. reported decreased levels of Dgcr8 and miRNA in the mouse prefrontal cortex during progression. As a result, the electrical characteristics of layer V pyramidal neurons were changed; excitatory synaptic transmission and basal neurite complexity were reduced (Schofield et al. 2011). Another study found that Dgcr8+/ knockouts exhibited changed electrical characteristics and smaller dendritic spines in later V pyramidal neurons. Furthermore, they detected fewer neurons in layers II and IV overall (Fénelon et al. 2011). It has also been discovered that Dicer and other members of the miRNA biogenesis family are prone to spontaneous copy number variation. A previous study found a duplication encompassing the DICER1 gene in a genome-wide scan for de novo CNVs in sporadic schizophrenia (Xu et al. 2008a), while another study noted that chromosome 8p (which includes 7 miRNA) is a CNV hot spot for schizophrenia and other illnesses including autism (Tabarés-Seisdedos and Rubenstein 2009). A high dose of the Dicer gene is associated with alterations in the expression of the Dicer gene linked to schizophrenia as seen in the DLPFC and increased expression of mature miRNA (Beveridge et al. 2010). Alterations in miRNA biogenesis have also been proposed by postmortem brain studies as a possible reason for miRNA deregulation in particular cohorts. Another study revealed that numerous miRNAs with downregulation also showed a decrease in the proportion of mature to the primary transcript, indicating that miRNA synthesis could be hindered (Perkins et al. 2007). In addition, it was found that several increased miRNA expressions had higher expression in their precursor transcripts in the investigations of BA9 and BA22/STG (Blow et al. 2006). A modified biogenesis of miRNAs was shown due to the increasing expression of miRNA. This was validated by a rise in the mRNA of DGCR8 in both locations (BA22/STG, BA9), as well as an elevation in the mRNA of DICER in the DLPFC. While using a paired statistical technique, it was also shown that mRNA levels of Drosha and DGCR8 had elevated proportionally in the BA46 cohort, in addition to the considerably higher levels of Dicer mRNA (Khavari and Cairns 2020).
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6.6 Pharmacological Impact Numerous studies have assessed how different neuroleptic medications affect miRNA expression. As most schizophrenia patients have received a long history of antipsychotic medication and the effects on the expression of miRNA are mostly unexplored, this seems to be especially important to consider when evaluating the results of post-mortem investigations (Beveridge and Cairns 2012). Perkins et al. compared the expression of three miRNAs including miR-128b, miR-199a, and miR-128a which were unregulated in the frontal cortex between haloperidol-treated rats and control rats who had not received the drug (Perkins et al. 2007). Interestingly, the author showed that the expression of miRNA was upregulated in several genes such as STG (miR-128a, miR-128b) and DLPFC (BA9) (miR-128a, miR-199a) of schizophrenia patients who have previously received haloperidol during therapy (Beveridge et al. 2010). In a similar study, another author reported the impact of sodium valproate and lithium, two most commonly used bipolar drugs, on the expression of miRNA in the hippocampus of rats (Zhou et al. 2009). Moreover, miR-24a, miR-30c, miR-34a, miR-221, Let-7b, and let-7c, as well as miR-128a, were found to be downregulated, while miR-144 was found to be unregulated, in both treatments all of these miRNAs have similar behavior (Beveridge and Cairns 2012). Additional investigation established a connection between miR-34a and metabotropic glutamate receptor 7 (GRM7) which is a putative target. Considering GRM7 being a promising therapeutic gene and miR-34a showing upregulation in schizophrenia patients’ PBMCs (Lai et al. 2011) and DLPFC (BA46) (Kim et al. 2010), this has a specific significance to schizophrenia. Using the specific NMDA receptor antagonists dizocilpine and MK-801, it was observed that miR-219 was lowered in the prefrontal cortex (Kocerh et al. 2009). It was demonstrated that miR-219 plays a part in NMDA signaling when its target, calcium/calmodulin-dependent protein kinase II gamma subunit (CAMKII), was overexpressed in the mouse brain while miR-219 was suppressed in vivo. As a result, it was found that aberrant CAMKIIγ expression hindered NMDA receptor signaling and triggered the associated behavioral reactions. Additionally, they depict that pre-treating the mice with clozapine and haloperidol could decrease the effects of dizocilpine/MK-801 on miR-219. The NMDA receptor hypoactivity theory of schizophrenia and the observation that miR-219 expression is higher in the DLPFC (BA9) of schizophrenia patients are in agreement (Beveridge et al. 2010).
6.7 Perspective of miRNA Therapeutics According to predictions, 20–30% of human genes are controlled through miRNAs (Dandekar and Dandekar 2007). miRNAs may be utilized as biomarkers or targets for clinical treatment and diagnosis because of their participation in a variety of psychiatric disorder-related challenges (Nadim et al. 2016; Mahmoudi and Cairns 2017). Even though, miRNA has a key role in brain development and has been well established, further research is still required to comprehend the regulation of miRNA mechanisms and their pathological implications in neuropsychiatric illnesses.
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Identifying the functional location of miRNAs in the human genome linked to schizophrenia remains the major challenge. There has been significant advancement in projects including the Encyclopedia of DNA Elements project (ENCODE), which intends to map every functional element in the human genome (ENCODE Consortium et al. 2013). The investigation of miRNA transcription patterns and their target genes in illnesses is made possible by new high-throughput techniques and RNA microarray methods including next-generation sequencing (NGS) (Sand et al. 2016; Pantazatos et al. 2017). By interacting with base pairs in the target mRNA’s 3′UTR and seed region, miRNAs control the expression of their target genes (nucleotides 2–7). The forecasting of efficient miRNA target regions is challenging yet will be crucial study; thus, a sequence of this length considerably more commonly will occur throughout the whole genome. Targets can and PicTar are currently the most sophisticated and widely used predicting tools. However, two- thirds of their anticipated targets seem to be unresponsive to the miRNA (Schmiedel et al. 2015). Therefore, it is unquestionably essential to develop or keep improving experimental techniques so as to comprehend the impact of miRNAs on their target genes. miRNA downregulation or upregulation may be a possible strategy in therapeutic intervention considering that miRNAs exhibit aberrant expression in several psychiatric diseases (Nana-Sinkam and Croce 2013; Pottoo et al. 2021; Hironaka-Mitsuhashi et al. 2022). It has taken a lot of effort to create oligonucleotide mimics or antisense oligonucleotides that are highly effective and non-toxic for regulating the levels of miRNA expression. Numerous chemical alterations were established to improve the constancy of the RNAs in association with these tasks, including locked nucleic acid (LNA) and 2′-O-methoxyethyl (Stenvang et al. 2008; Chabot et al. 2012). There is no proof of LNA-associated toxicity when LNA- antimiR-212 is systemically administered to the hepatic of African green monkeys. Instead, it results in a long-lasting and reversible reduction in the overall plasma cholesterol (Stenvang et al. 2008). LNA-antimiR-212 (SPC3659) is a therapy for chimpanzees with hepatitis C virus (HCV) infection that also inhibits HCV viremia for a long duration without causing any adverse reactions or showing any symptoms of resistant pathogens in the wildlife (Lanford et al. 2010). A miR-16-based miRNA mimic targeted to EGFR and packed in TargomiRs-EDVs was tested in a first-in- human trial on patients with malignant pleural mesothelioma. The findings demonstrated that TargomiRs were well tolerated at a dose of 5 × 109 weekly with full dexamethasone prophylaxis and were followed with preliminary evidence of anticancer efficacy. Since this study is open-label, a randomized phase 2 investigation with a bigger population is required to validate the findings (van Zandwijk et al. 2017). In the CNS, the blood–brain barrier (BBB) is the key challenging organ when evaluating this type of treatment for neurotherapeutics. By either drug alteration or connecting it to a vector, various strategies of drug delivery to the CNS have been established to enhance the capability of pharmacological compounds to penetrate the BBB (Hossain et al. 2010). Exosome mediators have numerous benefits as delivery vehicles when employed as a nano-delivery method (Alvarez-Erviti et al.
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2011; Yao et al. 2015). Exosomes, which are produced by a variety of mammalian cells, are the smallest homogeneous membranous vesicles. Because of their excellent delivery attributes, lack of immunogenicity, and capacity to pass through the BBB, exosomes are currently considered as effective delivery mediators for RNA treatment (Alvarez-Erviti et al. 2011). Exosomes have the potential to deliver miRNA to the CNS, but several researches are needed. A study reported that a brain-specific nano-carrier called RVG-SSPEI (rabies virus glycoprotein-disulfide related polyethyleneimine) was designed to efficiently transfect miR-124a in the brain of mouse (Hwang et al. 2011). Various other techniques have also been investigated, such as aptamers, nanotechnologies, chemical modification, and conjugation methods, as well as viral delivery systems (Cao and Zhen 2018). It remains challenging to evaluate the administered functional activity of miRNAs in those systems at the same time. However, specific delivery into the CNS is still difficult, despite the advancement in technology is very promising. Developing a reliable and effective miRNA therapeutic in clinical research will require a lot of effort.
6.8 Conclusion miRNAs have significant roles in the pathophysiology of schizophrenia, as shown by the investigation in their biogenesis and activities in the CNS. The specific profiles of miRNA alterations in schizophrenia patients and their relationship to prognosis and therapy response are still largely unknown. Further investigation should emphasize on finding distinct miRNAs associated with diseases and knowing their precise mechanisms for controlling biological pathways and impacts on pathological conditions. As a result of technological advancement, targeted miRNA delivery to the CNS might offer a new promising therapeutic strategy for the management of psychiatric illnesses including schizophrenia. Acknowledgments Authors are thankful to the Management and Principal of Dadasaheb Balpande College of Pharmacy, Besa, Nagpur (MS), India, for providing opportunity to work. Conflict of Interest The authors declare no conflict of interest.
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7
Muscular Dystrophy: Underlying Cellular and Molecular Mechanisms and Various Nanotherapeutic Approaches for Muscular Dystrophy Durafshan Sakeena Syed, Mohamad Sultan Khan, Urba Afnan, Mohd Jamaal Dar, and Tariq Maqbool
Abstract
Muscular dystrophy (MD) corresponds to a cluster of approximately 30–40 genetically controlled diseases, which exhibit inheritance patterns that are both dominant and recessive and can be autosomal or X-linked. These disorders are marked by gradual muscle degeneration and diminished muscle potency of variable severity depending on the stage and onset age of the disease, as well as the distribution of affected muscles. In most cases, patients ultimately lose the ability to walk, and unfortunately, no therapeutic or promising drugs have been discovered for MD to date. This chapter examines the genes and the corresponding proteins, which are responsible for the majority of these conditions, as well as various diagnostic and treatment strategies, focusing on the importance of D. S. Syed Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, USA M. S. Khan Neurobiology and Molecular Chronobiology Laboratory, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India U. Afnan Laboratory of Nanotherapeutics & Regenerative Medicine, Department of Nanotechnology, University of Kashmir, Srinagar, India Indian Institute of Technology (IIT) Bombay, Mumbai, India M. J. Dar Laboratory of Cell and Molecular Biology, Department of Cancer Pharmacology, CSIRIndian Institute of Integrative Medicine, Jammu, India T. Maqbool (*) Laboratory of Nanotherapeutics & Regenerative Medicine, Department of Nanotechnology, University of Kashmir, Srinagar, India e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_7
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nanotechnology-based approaches. This chapter aims to provide a comprehensive understanding of the basics, clinical symptoms, and molecular mechanisms underlying various types of MDs. Keywords
Muscular dystrophy · Dysregulation · Dystrophin gene · Autosomal recessive
7.1 Introduction Muscular dystrophy (MD) is a heritable, mostly non-inflammatory but devastating muscular disorder characterized by progressive degeneration resulting in reduced muscular strength, loss of overall muscle cell mass, and reduced mobility (Gorecki 2019). The term “dystrophy” was originally used to characterize it in the 1830s by Charles Bell. Its root words are Greek: dys, which means “no, un-,” and troph-, which means “nourish.” There is currently no treatment for MD (Gill 2022; Wilton-Clark and Yokota 2023); however, several drugs and treatments can help control the disease’s symptoms and reduce its development. Therefore, MD is an incurable myopathic disease that impairs movement and results in permanent muscle loss owing to shrinking as it progresses. Patients who are suffering from the disease’s final stages have trouble doing basic everyday tasks including walking, bathing, brushing their hair, and eventually even standing. Despite the tight physical link between skeletal muscle and nerves, MD, which is a disease of muscle degeneration, seldom affects the central nervous system or peripheral nerves. Additionally, this condition can harm important organs including the heart, liver, and lungs. The main indication of MD is a gradual reduction in muscle potency. Varied signs and clinical manifestations could appear at different stages of life within distinct muscle groups, depending on the MD type. Thus, specific forms of MD manifest during childhood, and some become apparent during middle adulthood and beyond. Mutations in the genes that produce the proteins required to make healthy muscles that are aberrant are the primary cause of muscular dystrophy. MDs are mostly X-linked or autosomal disorders displaying both recessive and dominant patterns of inheritance. In rare cases, the disorder may also be caused by a de novo or spontaneous mutation. Research has established that in MD patients, gracilis, semimembranosus, semitendinosus, and sartorius muscles can be affected (Diaz-Manera et al. 2015). Due to the X-linked nature of the disease, males are the prime victims (Brinkmeyer-Langford and Kornegay 2013). Turner syndrome, imbalanced silencing of X-chromosome during dosage compensation, the relocation of the mutated gene to an autosome, or inheritance of both chromosomal sets from the same parent (uniparental disomy), collectively contribute to the symptoms of illness in female offspring (Jackson et al. 2018). In
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general, affected females typically exhibit proximal muscle weakness during early childhood.
7.2 Types of MD More than 30 distinct types of MD exist. Those frequently observed include: 1. Duchenne muscular dystrophy (DMD) (Meryon’s disease) 2. Becker muscular dystrophy (BMD) 3. Myotonic dystrophy (DM) 4. Limb-Girdle muscular dystrophy (LGMD) 5. Facioscapulohumeral muscular dystrophy (FSHD) 6. Congenital muscular dystrophy (CMD) 7. Distal muscular dystrophy (DMD) 8. Oculopharyngeal muscular dystrophy (OPMD) 9. Emery–Dreifuss muscular dystrophy (EDMD) These classifications are based on the phenotype and the genotype. Furthermore, the kind of mutations, type of muscle affected, onset time, extent of severity, and degeneration period vary in different types of MD.
7.2.1 Duchenne Muscular Dystrophy (DMD) (Meryon’s Disease) Humans can get the severe and progressive illness Duchenne muscular dystrophy (DMD), which causes muscle loss. Initial symptoms include difficulty moving, and if it worsens, it may require aided breathing and cause early death (Duan et al. 2021a). DMD is the predominant pediatric MD and the most prevalent variety of MD currently recognized (Mendell and Lloyd-Puryear 2013; Emery et al. 2015; Crisafulli et al. 2020). It has been shown that although females are often carriers, boys are the ones who are most impacted by this illness (Song et al. 2011). The dystrophin gene (DMD), by far the biggest gene known in humans with 79 exons, is essential in preserving the structural integrity of the muscle. The X-linked recessive mode of inheritance for this gene is identified at the Xp21 region of the X chromosome’s smaller arm (p). Any mutation in the dystrophin gene (which codes for dystrophin) prohibits the development of the muscular isoform of dystrophin (Dp427m), resulting in a dystrophin protein that is not functional and causing muscle cell death and weakening (Aartsma-Rus et al. 2006). Between 3 and 5 years are required for the disease to manifest and it advances quickly. By the age of 12, the ability to walk is compromised in the majority of boys and they eventually become dependent on respirator-assisted breathing. There is a 50% likelihood that the girls in such families will inherit the faulty gene and pass it on to their offspring. DMD is an X-linked recessive disorder with an incidence ratio of 1 in 5000–1 in 6000 impacted male newborns. Patients with DMD can live longer with the right
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management, care, and cardiopulmonary dysfunction therapy (Ryder et al. 2017). The survival rate of those suffering from DMD has enhanced, with the 15.8 years of added lifetime, as the median lifespan projection improved from 25.77 to 40.95 years, before and after the year 1970, according to a survey conducted in France (Kieny et al. 2013). Before the identification of dystrophin and DMD, the fundamental processes of DMD remained a mystery, and a number of theories were put up. Muscle ischemia, defective motor neuron function, nutritional inadequacy, metabolic flaws, improper calcium regulation, and the sarcolemmal injury hypothesis were a few of the most significant ones (Duan et al. 2021a). The sarcolemmal theory became the most well- liked of them since it appears to explain many of the clinical signs of DMD. This theory states that a sarcolemmal protein’s structural or functional flaws are what cause DMD (Dongsheng et al. 2021). Later the origin of DMD was attributed to the dystrophin protein located beneath the muscle membrane and the DMD gene (Hoffman et al. 1987; Duan et al. 2021a). The DMD gene has various promoters that encode dystrophin protein in a tissue-specific manner. Dp427 produces full-length dystrophin where Dp427-M expresses in muscles, Dp427-C in cortical neurons and Dp427-P in the cerebellar Purkinje cells (Muntoni et al. 2003; Duan et al. 2021a). The Dp427-P, initially discovered in mice, is a cerebral isoform expressed postnatally and throughout embryonic development, however, in human’s expression is relatively less (Doorenweerd et al. 2017). Four internal promoters also generate some shorter dystrophin isoforms in addition to the full-length variants. The role of DMD and its protein have been separately discussed in Sect. 7.3. The dystrophin-associated protein complex (DAPC) disintegrates due to the deficiency of dystrophin, leading to an impaired connection between F-actin and the extracellular matrix. This disturbance holds considerable implications as the DAPC is responsible for critical roles in mechanics and communication, which contribute to maintaining the strength of the structure and the muscles’ ability to contract; therefore, its disintegration has a variety of negative effects on muscle cell function, including thinning of the sarcolemma (Duan 2018; Dongsheng et al. 2021), functional ischemia (Duan et al. 2021a; Dubuisson et al. 2022), free radical damage (Papadimas et al. 2022), cytosolic calcium overloading (Merckx and Paepe 2022; Dubinin and Belosludtsev 2023), and regeneration failure (Ganassi et al. 2022) leading to muscle degeneration.
7.2.2 Becker Muscular Dystrophy (BMD) BMD has a variable phenotype and a sluggish progression. Independent walking is never lost before the third decade, although beginning in childhood. Boys with Becker MD, a condition that is extremely similar to Duchenne MD but less severe, have defective or inadequate dystrophin. Both BMD and DMD have comparable origins and symptoms, and both of these illnesses are brought on by mutations in the Xp21-located dystrophin gene (DMD). BMD occurs due to in-frame deletions, mutations, or duplications in the dystrophin gene (Angelini et al. 2019). All individuals with aberrant dystrophin levels or sizes also exhibit clinical signs that are
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consistent with BMD. For the female carriers of mutations, respiratory abnormalities seldom occur, yet up to 13.3% of such individuals may experience dilated cardiomyopathy and the skeletal muscle phenotype. A number of “preclinical” or “asymptomatic” instances, in addition to conventional BMD cases, can be identified based on anomalies in the dystrophin protein or DMD gene variants.
7.2.2.1 Modes of Inheritance (Including Types) Males (XY) are biologically more prone to DMD as the copy number for the X chromosome is one. Therefore, the heritability of the disease will be more influenced by the genetic status of a mother (XX) (Nozoe et al. 2016). DMD heterozygous mutant females are carriers with a 50% probability of transmission to male children, they are mostly asymptomatic and occasionally have symptoms associated with BMD. DMD affects people with Turner’s syndrome, translocations including DMD, or bi-allelic DMD mutations, and it is extremely uncommon in females (1 per million) (Duan et al. 2021a; Rodriguez et al. 2022). In almost all instances involving DMD or BMD, instances of deletion, duplication, minor mutation, or substantial genomic rearrangements between an X-chromosome and a non-sex chromosome (autosome) have been documented. However, a few instances of DMD gene translocations have also been described, resulting in DMD. In the affected females (Ishizaki et al. 2018), it happens because of systematic inactivation of the unimpaired X chromosome. Due to the chromosomal translocation’s inactivation effect on the autosomal chromosome in these situations, only those cells will survive that have unimpaired and inactivated X chromosomes, even though they theoretically have the potential to express dystrophin. Females with the DMD gene affected due to translocation are unable to express dystrophin. Around 33.3% of DMD and BMD cases are attributed to newly occurring germline mutations (Yu et al. 2017). Notably, because of germline mosaicism, females with affected children have a greater probability to have more affected offspring, even if their somatic cells are normal. According to Helderman-van Den Enden et al. (2009) and Dinh et al. (2018), such germline mosaicism in oocytes and sperms can occur up to 14% of the time. To determine the risk of transmission, genetic counseling and testing might be carried out on families with known DMD mutations.
7.2.3 Myotonic Dystrophy (MD) MD diseases are genetically transmissible, dominant, multi-systemic autosomal disorders. DMs share symptoms of muscular dystrophy, stiffness, and debility, early-developing cataracts, metabolic endocrine dysfunction, an increased susceptibility to neoplasia, and arrhythmias (Meola and Cardani 2015; Johnson 2019; Garcia-Puga et al. 2022). This most common kind of adult MD is subdivided into two groups (Soltanzadeh 2022); Dystrophia myotonica type-1 (DM1), sometimes called Steinert’s disease: The trinucleotide “CTG” (cytosine–thymine–guanine) repeat sequence in the
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DMPK gene’s 3′ non-coding region on chromosome-19q13.3 experiences an abnormal increase in size, resulting in an expansion that is not stable, causing DM1 (Brook et al. 1992; Aslanidis et al. 1992; Cardinali et al. 2022; Soltanzadeh 2022). Although DM1 is more prevalent in people of European ancestry, it is also seen in people from the Middle East and Asian countries such as India, China, and Japan (Wood et al. 2018). Muscle feebleness in the peripheral limbs which makes it difficult to execute intricate manual tasks using the hands and the condition of foot drop leading to instances of falling are clinical symptoms of typical DM1 (Steinert’s disease). Proximal muscles may be affected in more severe instances, making it difficult to ascend stairs and reach above the head (Meola 2005). Additionally, it produces weakening in the craniofacial region, which results in aberrant low-lying or drooping of the upper eyelids (ptosis) and dysarthria (anomalous voice), swallowing difficulties (dysphagia), facial palsy, and obstructive sleep. It also affects and hinders the function of upper limb muscles, particularly the hands, as well as muscles of the head and neck, such as those involved in tongue movement and chewing, which causes pain. When paired with aspiration pneumonia, neuromuscular respiratory insufficiency can occasionally show as DM1, which necessitates extended stays in the critical care unit or invasive ventilation (Boentert et al. 2020). Cardiovascular problems, such as different dysrhythmias and heart blocks that result in unanticipated morbidity and death, are one of the main issues with DM1 patients. For this reason, people with DM1 require ongoing cardiac monitoring. In many situations, artificial pacemakers and other procedures are also necessary. Dystrophia myotonica type-2 (DM2), sometimes called PROMM (proximal myotonic myopathy), is distinguished from DM1 by the prominence of proximal muscle weakness in contrast to the weakening and wasting of muscles in the peripheral regions. The four nucleotide “CCTG” (cytosine–cytosine–thymine–guanine) repeats within the first intron of the cellular nucleic acid binding protein gene (CNBP), also referred to as the zinc finger 9 (ZNF9) gene’s first intron on chromosome 3q21.3, experiences an abnormal increase in size (75–12,000 repeats), resulting in an expansion that is not stable, causing DM2 (Thornton et al. 1994; Meola et al. 1996; Finsterer 2002; Chakraborty et al. 2016; Soltanzadeh 2022). Clinically identical to DM1, DM2 is a multi-systemic, clinically (but not genetically) diverse illness. Although three distinct DM2 phenotypes—PROMM, proximal myotonic dystrophy (PDM), and myotonic dystrophy 2 (DM2)—were initially identified, research has since shown that each of these phenotypes results from ZNF9 gene’s single mutation (Finsterer 2002). A solitary ancestral mutation has been identified in DM2 patients tracing back approximately 200–540 generations from German/North European lineage (Bachinski et al. 2003). Both DM1 and DM2 are characterized by aberrant splicing of a number of downstream effector genes, which has detrimental effects on a number of tissues and results in a variety of complicated and severe clinical symptoms. Heart, skeletal, and smooth muscles are most commonly impacted by this illness. In addition, DM1 mostly affects peripheral musculature experiencing a decline in type-1 fibers, while DM2 mainly impacts proximal musculature, resulting in a reduction of type 2 fibers (Meola 2020). Both kinds of DM are known to cause progressive multisystem degeneration or multiple organ failure, according to reports. Compared to DM2, DM1 is thought to have a
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more prevalent and severe phenotype. Additionally, according to Mathieu and Prevost (2012), DM1 stands as the most common form of MD with onset during maturity, impacting 1 in 8000 persons globally and current research indicates that the frequency of DM1 is around 48/100,000 (Johnson et al. 2021). It might be difficult to discern between DM1 and DM2 only based on clinical factors in some individuals due to their clinical similarities.
7.2.4 Limb-Girdle Muscular Dystrophy (LGMD) The term “limb-girdle muscular dystrophy” refers to a diverse range of disorders, mostly affecting the hips and shoulders’ voluntary muscles. According to Wicklund and Kissel (2014) and Johnson and Statland (2022), all of these conditions are autosomal; not related to FSH, muscle stiffness, peripheral, congenital, or symptomatic conditions. According to Nigro and Savarese (2014), LMGD is often divided into two categories: autosomal dominant and autosomal recessive LMGD.
7.2.4.1 Autosomal Dominant LGMD The autosomal dominant types, sometimes referred to as LGMD1, typically begin in adulthood. Since the afflicted people are often of reproductive age and in excellent health, these are typically thought of as the milder types of LGMD. Autosomal recessive LGMD cases account for fewer than 10% of the total, making them quite uncommon. The eight distinct autosomal dominant LGMD or LGMD1 varieties that have been discovered thus far (including LGMD1A-H) are mentioned below. LGMD1A: Myotilin (MYOT) gene mutations, which are located on chromosome 5 at location 5q31.2, are the cause of LGMD1A. Z-disk-associated protein is myotilin. LGMD1A is a rare variant of LGMD that is distinguished by late-onset proximal weakness followed by distal weakening. Some individuals speak with a nasal or dysarthric accent, and their blood creatine kinase (CK) values are somewhat higher. Rimmed vacuoles with or without inclusions can be seen in muscle pathologies. Z-line streaming is clearly visible in electron microscopy. According to Reilich et al. (2011), these individuals occasionally have cardiac and respiratory problems. LGMD1B: Lamin A/C (LMNA) gene mutations on chromosome 1 at 1q22 are the source of the condition. There are three isoforms of this gene, including lamin-A, A10, and C. The primary variants, namely lamin-A and C, play a variety of tasks, from mechanical, nucleus membrane maintenance to gene regulation. They form integral components of the fibrous nuclear scaffold. The LGMD1B is identified by asymmetric proximal onset of frailty in the leg muscles and is connected to dysrhythmias and problems in atrio-ventricular conduction. The patients’ CK values range from normal to slightly higher. Within 20–30 years, the majority of individuals experience proximal limb paralysis, heart arrhythmias, and abrupt death (Vincenzo et al. 2022).
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LGMD1C: The gene CAV3, known as caveolin 3, situated at locus 3p25.3 on chromosome 3, is the source of LGMD1C mutations. This gene produces Caveolin-3, a membrane protein that is particular to muscles and is the main building block of the caveolae membrane in muscle cells. Studies have shown that the only gene whose mutations can result in caveolinopathies is this one. Moderate-to-slight proximal muscular frailty, enlargement of the muscles in the calf region, a positive Gower sign, and diverse muscle cramps after physical activity are features of LGMD1C, which often manifests in the first decade (Gazzerro et al. 2011; Ohsawa et al. 2022). LGMD1D: The gene DNAJB-6, situated on chromosome 7q36.3, has heterozygous missense mutations that cause LGMD1D. The ‘J-domain’, a highly conserved sequence of amino acids, is what distinguishes the DNAJB6 protein family that this gene produces from others (Nigro 2003; Findlay et al. 2022). According to Chuang et al. (2002), these proteins serve as chaperones that function in a variety of physiological processes, such as protein folding and the production of different protein complexes. Heterozygous missense mutations in DNAJB6 (p.F-89-I, p.F-93-L, and p.P-96-R) result in inadequate protein folding clearance, which causes LGMD. Studies have shown that a mutant form of DNAJB-6 affects how another protein, BAG, interacts with the Z line of muscle, which in turn can induce myofibrillar myopathy (Lee et al. 2012). Protein aggregations including DNAJB-6 and its ligands, such as crystallin, desmin, filamin-C, HSAP-1, MLF-1, and myotilin, and the presence of autophagosomes is typical pathological findings of LGMD1D (Inoue et al. 2023). These aggregates are also seen in myofibrillar myopathy, indicating that the phenotypes of the two disorders are similar. Patients with LGMD1D have slightly higher blood CK levels and have lower limb involvement, especially in the adductor magnus, biceps femoris, semimembranosus, and soleus, but not in the heart or lungs. Some people continue to walk throughout their whole lives after the condition first manifests, with onset times ranging from 25 to 50 years (Nigro 2003; Findlay et al. 2022). LGMD1D: The gene DNAJB-6, situated on chromosome 7q36.3, has heterozygous missense mutations that cause LGMD1D. The “J-domain,” a highly conserved sequence of amino acids, is what distinguishes the DNAJB6 protein family that this gene produces from others (Nigro 2003; Findlay et al. 2022). According to Chuang et al. (2002), these proteins serve as chaperones that function in a variety of physiological processes, such as protein folding and the production of different protein complexes. Heterozygous missense mutations in DNAJB6 (p.F-89-I, p.F-93-L, and p.P-96-R) result in inadequate protein folding clearance, which causes LGMD. Studies have shown that a mutant form of DNAJB-6 affects another protein, BAG, and interacts with the Z line of muscle, which in turn can induce myofibrillar myopathy (Lee et al. 2012). Protein aggregations including DNAJB-6 and its ligands, such as crystallin, desmin, filamin-C, HSAP-1, MLF-1, and myotilin, and the presence of autophagosomes are typical pathological findings of LGMD1D (Inoue et al. 2023). These aggregates are also seen in myofibrillar myopathy, indicating that the phenotypes of the two disorders are similar. Patients with LGMD1D have slightly higher blood CK levels and have lower
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limb involvement, especially in the adductor magnus, biceps femoris, semimembranosus, and soleus, but not in the heart or lungs. Some people continue to walk throughout their whole lives after the condition first manifests, with onset times ranging from 25 to 50 years (Nigro 2003; Findlay et al. 2022). LGMD1E: Dilated cardiomyopathy type 1F (CMD1F) is another name for it. The splice mutation, in the third intronic region, known as (IVS3 + 3A → G) occurs in the desmin encoding DES gene that is situated at 2q35, which was once thought to be associated with chromosome 6q23. Such individuals exhibit gradual muscle frailty in the proximal parts beginning at 20–30 years of age, along with dilated cardiomyopathy and conduction abnormalities. Family relatives have a habit of passing away unexpectedly. According to Greenberg et al. (2012) and Nigro and Savarese (2014), serum CK is only slightly raised (150–350 U/L), and muscle tissue analysis could exhibit degenerative alterations that indicate the existence of granulo-filamentous inclusions near the nucleus or beneath the muscle cell membrane. LGMD1F: The underlying cause of this condition is the presence of a frame-shift mutation in the TNPO3 gene. This gene encodes transportin 3 found in skeletal muscle. Due to the missing expected stop codon, the mutant TNPO3 protein is bigger than the wild type (Costa et al. 2020). Early-onset adolescent patients exhibit a more severe phenotype and a faster progression of the disease than do those with adult onset. The vastus lateralis and iliopsoas muscles in particular exhibit significant atrophy, which is a hallmark of the condition. Without cardiac involvement, some individuals also exhibit the symptoms of dysphagia, arachnodactyly, and respiratory insufficiency (Peterle et al. 2013; Costa et al. 2020). LGMD1G: The underlying cause of this condition is the deficiency mutation in the gene HNRPDL, which is situated at chr4q21 (Vieira et al. 2014). This particular gene consists of eight exons and is expressed throughout various tissues. The resulting protein, HNRPDL, belongs to the RNA-binding protein family and plays a crucial role in mRNA biogenesis and metabolic processes. Patients have growing limits in the bending of their fingers and toes that develop over time (Starling et al. 2004; Vieira et al. 2014). LGMD1H: It develops as a result of mutations in the LGMD1H a new form of LGMD gene, which is located within a 25 cM area on the short arm (p) of chromosome 3, spanning from position 23 to position 25.1. The actual source of the illness is unknown; however, the majority of these individuals exhibit muscle frailty affecting both the upper and lower limbs in the proximal regions that begin around in the 40s or 60s and worsen with time (Bisceglia et al. 2010).
7.2.4.2 Autosomal Recessive LGMD The cumulative prevalence of the autosomal variants (LGMD2) is 1:15,000. There are recessive genes in which the loss-of-function mutations on both alleles typically result in an LGMD phenotype (ordinary LGMD genes): they correspond to the first nine forms of LGMD2 (LGMD2A–2H,2L). A variety of mutations show phenotypic heterogeneity.
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On the other hand, certain mutations in other genes (occasional LGMD genes) determine a more complicated illness whereas others are connected with LGMD. The other types of LGMD (LGMD2I–2W) are induced by distinct alterations in intermittent LGMD genes (Nigro 2003; Nigro and Savarese 2014). LGMD2A: Calpain 3 (CAPN3) gene mutations on chromosome 15q15.2 are the root cause of LGMD2A. According to Pathak et al. (2010), it is the most prevalent type of LGMD globally. Calpain 3, a 94 kDa protein unique to muscles, is encoded by this gene. These calpains are cysteine proteases (enzymes) that are non-lysosomal and intracellular that are controlled by calcium ions. Instead of “breaking down,” calpains alter the characteristics of target proteins by cleaving them (Pathak et al. 2021). LGMD2B: According to Nigro and Savarese (2014), it is brought on by a missense or null mutation of the DYSF gene, that encodes dysferlin, positioned on the short arm (p) of chromosome 2 at location 13.2. It encodes Dysferlin, a widely distributed 230 kDa transmembrane protein that is essential for calcium-mediated sarcolemma resealing. In many nations (but not everywhere), LGMD2B represents the second-most prevalent variant of LGMD2 (approximately 15–25%). Any DYSF gene mutation is linked to a variety of clinical profiles, from severe functional impairment to moderate late-onset variants. According to Nguyen et al. (2007) and Rosales et al. (2010), polymyositis is clinically misdiagnosed in around 25% of patients. LGMD2C–F: LGMD2D, 2E, 2C, and 2F result from mutations that lead to the loss of function in the genes responsible for producing the sarcoglycan complex components: α, β, δ, and γ in the skeletal muscle. Chromosomes 17q21.33, 4q11, 13q12.12, and 5q33.3, respectively, each contain these genes. Sarcoglycans are membrane-spanning proteins that undergo glycosylation on the N-terminus and possess an extensive extracellular domain and a cluster of conserved cysteines, and are parts of the dystrophin complex. Sarcoglycanopathies have an early beginning akin to the dystrophinopathies of the intermediate type (Nigro and Savarese 2014). LGMD2G: The LGMD2G results from a homozygous nonsense mutation in the TCAP gene, that encodes the titin cap/Telethonin protein (TCAP), which spans 1.2 kb of genome and is positioned on the long arm (q) of chromosome 17 at location 12. TCAP, a 19 kDa protein, is present in both cardiac and striated muscle. It is a substrate of titin kinase and attaches to the titin Z1–Z2 regions. These interactions are crucial for sarcomere construction (Hernandez-Lain et al. 2016). With calf hypertrophy and cardiomyopathy, these individuals exhibit adolescent- onset weakness that impacts the muscles near the pelvis first, gradually extending to the muscles in the lower legs. One of the most uncommon types of LGMD is LGMD2G (Knoll et al. 2002). LGMD2H: The LGMD2H results from a mutation in the Tripartite motif containing gene-32 (TRIM32) that produces a 673 amino acid-containing protein, which is positioned on the long arm (q) of chromosome 9 at location 33.1. Although its role is unclear, bioinformatic analysis suggests that it could be an E3-ubiquitin
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ligase. This disorder usually appears later in life, featuring proximal muscle frailty and atrophy, and adequately elevated CK levels (Locke et al. 2009). LGMD2I—P: In all these cases, genetic variations or mutations reduce glycosylation of dystroglycan, causing milder inborn MDs or an array of more severe multi-systemic symptoms encompassing brain and ocular abnormalities like the Walker–Warburg syndrome or muscle–eye–brain disease. LGMD2I: The LGMD2I results from a mutation in the 12 kb gene, FKRP, that produces Fukutin-related protein, which is positioned on the long arm (q) of chromosome 19 at locus 13.32 (Brockington et al. 2001). Due to a glycosylation deficiency, this dystrophy is connected to alterations in alpha-dystroglycan expression. At least, 10% of all instances of LGMD are thought to be caused by LGMD2I mutations, making them a reasonably prevalent cause of the disease. Congenital muscular dystrophies and LGMD2I both involve the portion of the dystrophin/utrophin-associated complex situated outside the sarcolemma (Stensland et al. 2011). LGMD2J: The LGMD2J results from a mutation in the titin (TTN) gene, spanning a large 294.442 kb of the genome which is positioned on the long arm (q) of chromosome 2 at locus 31 (Nigro 2003; Nigro and Savarese 2014). The biggest protein in the human genome, titin, is encoded by it (Marcello et al. 2022). Within the myofibrils of striated muscle, this protein establishes an unbroken filamentous network, stretching from the Z-disc to the M-band in the sarcomere. The underlying cause of this MD is a homozygous mutation that involves 11 bp deletion or insertion (FINmaj) at the C-terminus domain. Another protein, CAPN3, exhibits a secondary deficit in LGMD2J patients by binding to M-band titin in the area where LGMD2J mutations occur (Sarparanta et al. 2010). LGMD2K: This MD results from a hypomorphic missense mutation in the gene POMT1, which is positioned on the long arm (q) of chromosome 9 at locus 34. Deficits in glycosylation of dystroglycan protein (MDDGC1) caused by distinct POMT1 variants lead to inborn MDs encompassing significant ocular and brain anomalies (Mercuri et al. 2009). LGMD2L: This MD results from mutations in the TMEM-16E gene (also known as anoctamin-5, ANO-5, and GDD-1) at 11p14.3 (Bolduc et al. 2010). Anoctamins, a class of calcium-activated chloride channels, are the protein byproducts of this gene (Tian et al. 2012). In Northern Europe, LGMD2 is one of the most prevalent LGMDs, accounting for 10–20% of cases, with the most prevalent mutation being in the coding region of exon 5 involving duplication of A at the locus 191 (Hicks et al. 2011; Witting et al. 2013). The condition often manifests in maturity, at which stage individuals experience frequent quadriceps wastage, uneven muscle engagement, and discomfort after activity. Additionally, these individuals have elevated CK levels (5- to 20-folds), while the heart and lungs are unaffected. LGMD2M: This MD results from a mutation in the gene FKTN that produces fukutin protein, which is positioned on the long arm (q) of chromosome 9 at locus 31.2 (Godfrey et al. 2006). The CNS is unaffected and intellect is unaltered in LGMD2M. Patients have widespread and symmetrical muscular involvement,
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which gets worse with acute febrile illness, increased CK values (10–50×), spinal stiffness, contractures, breathing difficulties, and cardiac muscle degeneration. LGMD2N: This MD results from a mutation in the gene POMT2, which is positioned on the long arm (q) of chromosome 14 at locus 24 and contains 21 exons (Biancheri et al. 2007). In most cases, there are high-impact symptoms including muscle ocular brain-like disorders and Walker–Warburg syndrome (Godfrey et al. 2007), although LGMD is very infrequently linked to them (Saredi et al. 2014). The mutations in these situations frequently result in decreased dystroglycan glycosylation, LGMD without brain damage, and very elevated blood CK levels. LGMD2O: It is linked to less severe mutations at chr. 1p32 in the POMGnT1 gene (Clement et al. 2008). Typically, POMGnT1 gene mutations are linked to acute symptoms including Walker–Warburg syndrome. LGMD2P: This MD results from mutations in the DAG1 gene that encodes dystroglycan (Nikhanj 2022). It prevents the maturation of O-mannosyl glycan residues with phosphorylation on dystroglycan, in a LARGE-dependent manner, which affects the molecule’s ability to bind to laminins and causes dystroglycanopathies. Even though the dystroglycan gene may be normal, the mutations affecting its glycosylation lead to these problems. LGMD2Q: This MD results from homozygous 9 base pair deletion in the gene Plectin (PLEC1), which is positioned on the long arm (q) of chromosome 8 at locus 24.3. The AUG codon, which is exclusively found in the muscle-specific transcript Plectin 1f, is impacted by the deletion. Patients with LGM2Q generate normal skin plectin without any associated skin pathology and have early-onset, non-progressive muscular weakness (Zhong et al. 2017). LGMD2R: This MD results from mutations in the DES gene, which encodes desmin, that is a muscle-specific member of the intermediate filament (IF) protein family. Two Turkish siblings with consanguineous parents have been found to have a homozygous splice site mutation in the DES gene’s intron 7 (c.1289-2A>G), which adds 16 amino acids from residue 428. The mutation is localized at 2q35 (Maggi et al. 2021). Other mutations have now been discovered. Gradual weakening of muscles near the body’s core and generalized reduction in size, impacting both the upper and lower extremities first appear in the patients in their teens or early 20s. Ck serum levels are normal. A-V conduction blockages are typically seen in LGMD2R individuals, but no cardiomyopathy (Angelini and Fanin 2013). LGMD2S: This MD results from a mutation in the TRAPPC11 gene, which encodes transport protein particle complex 11, positioned on the long arm (q) of chromosome 4 at locus 35 (Koehler et al. 2017). In mammals, the ER-to-Golgi intermediate compartment is reached by anterograde membrane transport including the transport protein TRAPPC11. The two mutations (c.1287+5G>A and c.2938G>A/p.Gly980Arg) that have been discovered thus far affect the TRAPP complex’s composition as well as the shape of the Golgi and cell trafficking. A steadily advancing form of MD beginning in childhood, accompanied by ele-
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vated CK levels and neurological impairment, is one of the LGMD2S phenotypes (Nigro and Savarese 2014). LGMD2T: This MD results from a mutation in the gene GMPP-B, encoding GDP- mannose pyrophosphorylase-B, present on chromosome 3p21 (Oestergaard et al. 2016). Only a small number of people have had LGMD and inborn MDs due to hypo glycosylation of dystroglycan caused due to missense mutations, for instance, pD27H and p.V330I. Intellectual impairment and microcephaly were noted in a small number of individuals of Indian and Egyptian ancestry. All of these individuals had high CK values, and a muscle biopsy revealed that DAG1 was not properly glycosylated. A 6-year-old English male patient showed exercise intolerance and high CK levels (3000 U) (Nigro and Savarese 2014). LGMD2U: This MD results from a mutation in the gene ISPD, encoding isoprenoid synthase domain-containing protein, which is positioned on the short arm (p) of chromosome 7 at locus 21 (Taghizadeh et al. 2019). The LGMD2U mutations alter dystroglycan mannosylation, resulting in Walker–Warburg syndrome, severe cobblestone lissencephaly, and Walker–Warburg syndrome. The majority of patients with LGMD2U experience ambulation loss in the early adolescent years. A number of people have tongue-related muscular pseudohypertrophy. Additionally, respiratory and cardiac functions deteriorate, similar to other dystroglycanopathies (Van den Bergh et al. 2016; Liewluck and Milone 2018). LGMD2V: This MD results from a mutation in the gene GAA, encoding acid alpha-glucosidase, which is positioned on the long arm (q) of chromosome 17 at locus 25.3 (Van den Bergh et al. 2016). Acid alpha-glucosidase (GAA), a 953 aa protein, is encoded by the gene. Glycogen storage disease type 2 (GSD2) is brought on by GAA defects and results in LGMD. Late-onset similar to limb- girdle muscular dystrophy, Pompe illness may first manifest during the early 20s as increasing proximal muscle weakening in the lower limbs (Van den Bergh et al. 2016; Liewluck and Milone 2018). LGMD2W: This MD results from a mutation in the genes LIM and LIMS2/ PINCH2 encoding senescent cell antigen-like-containing domain protein 2, which is positioned on the long arm (q) of the second chromosome at locus 14. These 341 amino acid long focal adhesion family proteins control cell shape and migration and have LIM homeodomain and Zinc-finger domains. Such individuals have a juvenile beginning, profound quadriparesis, reduced ejection fraction, calf enlargement, macroglossia, notable preservation of facial muscles, and worldwide left ventricular failure in their third decade. They also have a distinctive broad-based triangular tongue (Taghizadeh et al. 2019).
7.2.5 Facioscapulohumeral Muscular Dystrophy (FSHD) FSHD is the third most frequent MD, coming behind DMD and DM. It is a progressive muscular dystrophy that causes lifelong morbidity, walking loss, and muscular fiber necrosis and atrophy. The most prevalent early symptoms include weakening of the core muscles associated with stabilizing the scapula and trouble extending the
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arms beyond shoulder height, frailty of distal muscles in the leg, and muscles used for facial expression (Tawil and Van Der Maarel 2006; Statland 2020). The clinical severity of this disease ranges from asymptomatic individuals to fully wheelchair- dependent ones. On chromosome 4q35, a repetitive region known as D4Z4 is deleted, which causes FSHD. The D4Z4 repeat in healthy people has 11–100 repetitions, each of which is 3300 base pairs. However, individuals with autosomal-dominant forms contain a single formation of 1–10 units (Tawil 2008). The presence of a minimum of one repetitive region D4Z4 from chromosome 4 is required for FSHD development, not just a monosomy of 4q. It is plausible that the deletion linked to FSHD might cause a detrimental gain of function (Hicks et al. 2011; Sacconi et al. 2015). FSHD type-1 (FSHD1) and type-2 (FSHD2) have similar phenotypes but different genotypes and epigenetics. FSHD1: is an inherited condition where the dominant genetic trait leads to chromatin relaxation, triggered by the abnormal contraction of repetitive region D4Z4 near subtelomeric region at 4q35 accounting for around 90–95% of the affected population (Van der Maarel et al. 2011; Sacconi et al. 2015). A coding sequence for DUX4 is found within every D4Z4 repeat (Dixit et al. 2007). Failure to silence DUX4 expression is linked to FSHD in differentiated muscles. Therefore, FSHD1 is often referred to as a “repeat contraction” condition. Chromosome rearrangements and 98% homologous regions between 4q and 10g (Sacconi et al. 2015) might make it more difficult to diagnose FSHD1 and lead to false- negative or false-positive findings. FSHD2: This type of FSHD (manifest in 5–10% individuals) results from a heterozygous mutation in the gene SMCHD1, required for dosage compensation and X-inactivation, which is positioned on the short arm (p) of chromosome 18 at locus 11.32 (Sacconi et al. 2015). The probable cause is haplo-insufficiency of SMCHD1 resulting from loss of function. Hence, FSHD2 necessitates the presence of both an SMCHD1 copy-inactivating mutation and a compatible 4qA variant (Larsen et al. 2015; Sacconi et al. 2015). Hypomethylation on chromosome 4 has been found in both FSHD1 and SHD2 patients, indicating a shared pathophysiological route in both diseases (de Greef et al. 2009). According to chromatin studies performed on FSHD2 patients, D4Z4 chromatin relaxation exists and promotes the expression of DUX4-fl (Tsumagari et al. 2011). Since the underlying pathophysiology of FSHD is still unknown, numerous non-pharmacological therapies can help with symptoms and functional improvements, but no disease-specific therapeutic approaches have been discovered to date.
7.2.6 Congenital Muscular Dystrophy (CMD) CMDs are a diverse collection of muscular illnesses characterized by the extremely early start of muscle weakening and, occasionally, by serious brain involvement. Muscle abnormalities have a histological pattern that is typical of dystrophic lesions,
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although it can vary greatly depending on the disorder’s severity and its various phases (Falsaperla et al. 2016; Arreguin and Colognato 2020; Zambon and Muntoni 2021). The early start of muscle frailty within the span of a single year of life, the manifestation of more or less severe newborn hypotonia, and the histological presentation of dystrophic lesions are all characteristics of this unusual category of MD diseases (Bonnemann et al. 2014). According to the disease’s stage or severity, the muscles of such individuals exhibit significant variations in histological investigations. Although the frequency of CMDs is unknown, it is usually believed to be between 1/100,000 people (Cavallina et al. 2023). Clinical characteristics, genotyping, and phenotyping are utilized to categorize CMDs, and molecular analysis is frequently employed for diagnosis. Dystroglycanopathies, which are also known as alpha-dystroglycan-related MDs, are covered in this chapter. These disorders include the most severe forms of CMDs, such as FCMD, MEB illness, and WWS (Bonnemann et al. 2014; Falsaperla et al. 2016). One circumstance that may result in CMDs is the improper glycosylation of alpha-dystroglycan (Reed 2009). Numerous genes including POMT-1, -2, POMGnT, Fukutin, FCMD, and LARGE, which lead to protein glycosylation as they produce particular or potential glycosyl- transferases, have been linked to the pathogenesis of alpha-dystroglycanopathies (Falsaperla et al. 2016). CMDs are typically linked to cerebral structural engagement and intellectual delay (ID) (Messina et al. 2010).
7.2.6.1 Fukuyama Congenital Muscular Dystrophy (FCMD) This MD results from a mutation in the gene FCMD or FKTN located on chromosome 9q31–33 coding for a 461 a glycosyltransferase called fukutin (Toda et al. 2000; Saito 2019). Hypotonia with exceptionally early onset facial muscle weakness, joint contractures, hypokinesia, and proximal muscles exhibiting slightly greater impairment compared to the farther ones are some of the clinical hallmarks of FCMD. In addition, over 50% of patients had pseudohypertrophy of the skeletal muscles and some showed signs of mental and verbal delay, febrile or afebrile seizures, and febrile or afebrile convulsions. These patients also experience severe muscular atrophy and degeneration, as well as high levels of connective tissue proliferation, particularly in the endomysium, delayed motor development, absent or reduced engagement of facial muscles, reflexes in deep tendons, and higher serum CK activity (Murakami et al. 2012). According to Ishigaki et al. (2018), imaging investigations of the central nervous system (CNS) show pachygyria/lissencephaly type II, irregularities in the cerebellum, and underdeveloped brain stem. Decreased muscle tone, limited psychomotor development, and visual indications such as nystagmus with glaucoma apprehension are all present in FCMD patients (Saito 2019; Agarwal et al. 2022). Although the clinical signs of FCMD and muscle–ocular– brain (MEB) syndrome are similar, FCMD has less severe ocular involvement. 7.2.6.2 Muscle Eye Brain (MEB) Disease This MD results from an autosomal recessive mutation in the gene POMGnT1, that produces a glycosyltransferase, which is positioned on the short arm (p) of the first
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chromosome at locus 34–32. Muscle–eye–brain is known as “MEB disease” (Taniguchi et al. 2003; Endo 2019) and is characterized by structural ocular and cerebral anomalies. In MEB, c.1814G>A (p.R605H) was the most prevalent mutation identified in 66% of cases. These individuals have hypotonia, limited psychomotor development, and visual indications such as nystagmus with glaucoma apprehension. All of these patients exhibit myoclonic jerks and convulsions. Facial dysmorphism, which manifests as a high, prominent forehead, a broad fontanel, a flat midface, and a short nose and filtrum, has also been observed in certain cases. Additionally, these patients have hypoplastic choroid, optic atrophy, optic coloboma, congenital glaucoma, and elevated levels of blood creatine phosphokinase (CK). These individuals’ eyes had cataracts, corneal opacity, and anterior chamber dysgenesis as their eye abnormalities. Agyric hemispheres, polymicrogyria in numerous cortical regions, and significant cortical disorganization have all been observed in MRI findings of these individuals (Valanne et al. 1994; Zambon and Muntoni 2021).
7.2.6.3 Walker–Warburg Syndrome (WWS) WWS is reported to be the most severe, genetically heterogeneous, and autosomal recessive disorder involving genes like POMT-1, -2, and less frequently POMGnT1, Fukutin, FKRP, and LARGE (Vajsar and Schachter 2006; Mercuri and Muntoni 2012). Since the majority of children do not live through their early years of life, symptoms are very severe (Balci et al. 2005). Lissencephaly type I is characterized by a surface resembling cobblestone, fusion of brain hemispheres, blockage of cerebrospinal fluid flow leading to hydrocephalus, misplaced neurons, absence of the corpus callosum, and underdevelopment of the pontine and cerebellar structures along with the expansion of the fourth ventricle are all signs of a persistent brain abnormality (Jung and Nagiel 2024). Additionally, people with this condition experience hypotonia, atrophy, and elevated CK levels. Recent research has revealed that the B3GALNT2 gene’s compound heterozygous mutations on the short arm (p) at various positions, c1068dupT—an alteration that leads to premature stop codon affecting D357, c1052T>A—premature stop codon affecting L357, which results in the production of disease-promoting truncated protein, c1A>G, affecting M1V— probable disease-promoting mutation in WWS (Wang et al. 2022). The Dandy–Walker cyst and eye abnormalities such as occipital encephalocele, retinal detachment, underdeveloped optic nerves, cataract, megalocornea, deformity in the iris, and total blindness are among the frequent clinical characteristics (Amiji et al. 2019; Jung and Nagiel 2024). Apart from WWS, FCMS, and MEB, additional rarer forms of CMDs within the category of dystrophies linked to dystroglycan comprise: Congenital muscular dystrophy type 1C (MDC-1C): This MD results from a mutation in the gene FKRP, a fukutin family protein located at 19q13.3. Although brain and cognition seem normal, cardiac and respiratory impairment, frailty of shoulder girdle, enlargement and diminished strength in the muscles of the legs, accompanied by the increased size of the calf and thigh muscles, are observed in youth with MDC-1C (Awano et al. 2021).
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CMD with partial merosin deficiency (MCD-1B): This variation is characterized by inconsistent presence of the glycosylated aDG, along with secondary deficiencies in laminin-α-2. Symptoms of muscle engagement include the premature onset of respiratory difficulties, proximal limb girdles frailty, muscular enlargement, particularly in the calf region (Falsaperla et al. 2016). Large-related CMD (MDC-1D): The exact genetic cause of this disease is not clear. However, various candidate loci based on linkage analysis include long arm (q) of chromosomes 1, 6, and 9 at positions 32, 2, and 31, respectively. The patients had pronounced levels of CK (between 200 and 700 U/L), generalized muscle weakness, including face muscles, and histological changes consistent with muscular dystrophy. Drooping of the eyelids, frailty in regulating eye movement, slight underdevelopment of the cerebellum, and minor cognitive impairment are all noted in these individuals’ MRI results (Clarke et al. 2011). Neonatal hypotonia: This MD results from diverse causes and conditions characterized by infantile reduction in muscle tone. These conditions may involve abnormalities in the central- or peripheral nervous system, range spanning from nerves to neuromuscular junctions and muscles (Sparks 2015).
7.2.7 Distal Muscular Dystrophy (DD) This MD comprises a set of hereditary primary muscle illnesses that mostly affect the distal parts of limbs, hands, or feet, causing gradual weakening and atrophy. More typically than the sarcolemmal protein deficiencies linked to proximal muscle dystrophies, the genes causing distal phenotypes appear to affect sarcomeric proteins. There are several varieties of DDs, and the following are a few of them in brief. Desminopathy: It is an autosomal dominant subtype of DD caused due to the Desmin gene mutation, present at 2q35. Early symptoms include weakness in the anterior lower leg, scapula, and heart complications such as cardiomyopathy (Barresi et al. 2012). Distal dysferlinopathy: It is an autosomal recessive subtype of DD involving the Dysferlin gene located at 2p13. The condition first manifests as weakness in the calf muscles and posterior lower legs. Such individuals have CK serum levels that are very high (10–100×) (Pozsgai et al. 2021; Spadafora et al. 2022). GNE-mutated DMRV-Nonaka distal myopathy: This DD is a recessive, autosomal disorder, also known as Miyoshi myopathy involving the gene GNE at 9p1- q1. The anterior lower legs’ muscles are the first to exhibit weakness. In these cases, higher (1–5×) serum levels of CK are seen (Udd 2014). Tibial muscular dystrophy: It is an autosomal dominant type of distal dystrophy also known as Udd distal myopathy caused due to defects in gene Titin located at 2q31 characterized by elevated (1–3×) CK levels in serum (Udd and Hackman 2020). Distal myosinopathy: It is an autosomal dominant type of distal dystrophy caused due to defects in gene MYH7 located at 14q. Type 1 fiber atrophy in the transversus abdominis muscles is a symptom of muscular disease. The levels of serum
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CK are increased (1–8×). Early signs include anterior lower leg weakness (Muelas et al. 2010). Laing myopathy: Also known as ZASpopathy and is an autosomal dominant type of distal dystrophy caused due to mutations in gene ZASP located at 10q. Early signs include lower leg weakness in the front. Higher levels of CK (1–3×), large vacuoles, and sarcoplasmic black masses are seen (Olive et al. 2016). Markesbery–Griggs myopathy: It is an autosomal dominant type of distal dystrophy caused by alterations in the sarcomere-associated PDZ motif-containing protein (ZASP), encoded by LDB3 gene that interacts with myotilin It is also known as distal myotilinopathy. Early symptoms include weakness in the posterior lower leg (Steiner et al. 2018). Distal nebulinopathy: This DD is an autosomal disorder with recessive trait, resulting from the alterations in gene Nebulin located at 2q21. Early symptoms include weakness in the anterior lower leg and the patients show higher (1–3×) serum CK levels (Amato and Griggs 2011). Vocal cord and pharyngeal distal myopathy (VCPDM): It is an autosomal dominant type of distal dystrophy caused due to mutations in gene Matrin3 (MATR3) located at 5q31.2. Dysphonia and weakness in the hands and anterior lower legs are early indications. Such patients have elevated serum CK levels (1–3×) (Yamashita et al. 2015). Welander-distal myopathy (WDM): This DMD is characterized by conditions encompassing pes cavus (foot deformity) and reduced reflexes in response to stimuli (Areflexia), DD emerging in adulthood, early-onset DD in adults, a form of adult-onset distal myopathy known as MPD3, DD with variable onset, and DD that leads to respiratory impairment are some additional subtypes of distal myopathy caused by unknown genes.
7.2.8 Oculopharyngeal Muscular Dystrophy (OPMD) OPMD results from specific engagement of the muscles in the eyelids and pharynx, causing drooping of the eyelids (ptosis) and difficulty in swallowing (dysphagia). The average age at which ptosis and dysphagia first appear in people with typical OPMD is 48 and 50 years old, respectively. Between 5% and 10% of individuals experiencing critical OPMD symptoms begin prior to the age of 45, which is associated with weakness in the lower limb girdles that first appears at the age of 60. Poor nutrition and potentially fatal aspiration pneumonia are risks that are increased by swallowing problems, which affect prognosis (Brais 2011). Other symptoms as the condition worsens might be a restriction of the upward direction of the gaze, mastication issues, trophy and frailty of the tongue, the
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presence of a wet or moist vocalization, alternative options include frailty of the face, axial and proximal limb girdle muscles, mainly the lower limbs. Over time, some people with significant involvement will require a wheelchair (Brais 2011; Trollet et al. 2020). OPMD is often inherited autosomally dominantly and seldom autosomally recessively. Both times, the PABPN1 gene, encoding polyadenylate-binding protein nuclear 1 gene, situated at the long arm (q) of chromosome 14 at position 11.2, experiences a brief (GCN) 11–17 expansion. A GCN expansion in the exonic region of PABPN1 might be heterozygous (affecting about 90% of affected people) or homozygous (affecting about 10% of affected people) (Semmler et al. 2007).
7.2.9 Emery–Dreifuss Muscular Dystrophy (EDMD) This MD is infrequent and involves muscle weakness, cardiac conduction abnormalities and cardiomyopathy, and early contractures (Heller et al. 2020). Depending on the subtype and person, these signs might be present or severe. Several genes associated with EDMD include emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, LUMA, SUN1, SUN2, and titin. These encompass EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, respectively. Due to the numerous life-threatening cardiac consequences, EDMD is very critical to identify. The aforementioned EDMD subtypes, such as EDMD1–7, result from the mutations linked to the aforementioned genes. The most frequent genetic causes of EDMD are mutations in LMNA and EMD together, which account for around 40% of cases (Meinke et al. 2011; Brull et al. 2018). EDMD commonly arises due to a deficiency or dysfunction in one or multiple proteins constituting the nuclear envelope, designated as nuclear envelopathy. Protein import into the nucleus may be lost, which might represent a common illness mechanism (Astejada et al. 2007; Busch et al. 2009; Kelkar et al. 2015). Early contractures, increasing muscular weakening and atrophy, and heart abnormalities are the clinical hallmarks of the typical type of EDMD. The first decade of life sees the emergence of these contractures, which become more pronounced around the 20s–30s (Madej-Pilarczyk 2018). A “humeroperoneal” pattern of weakness frequently affects the distal legs (primarily the peroneal muscles) and upper arms, especially the biceps and triceps muscles (Bonne et al. 2000). The patient’s neck may become stuck in an extended posture as a result of their impact on the paraspinal ligaments and posterior cervical musculature. The neck structure may change as a result of the cervical spine stiffness,
X linked DMD Xp21
X linked DMD Xp21
Autosomal MT-PK/ MDPK/ DMPK ZNF9 3q21.3
Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
Myotonic dystrophy (MD)
Type of MD (short form)
Inheritance Gene involved Gene location
MT-PK/ MDPK/ DMPK ZNF9
DMD
DMD
Deficient protein
Table 7.1 Detailed list of various muscular dystrophies
20 (more severe) to 40 years
Adolescence to early adulthood
2–6 years
Onset of phenotype Frequent falls, difficulty in rising after lying or sitting, trouble in running and jumping, waddling gait, walking on the toes, large calf muscles, muscle pain and stiffness, learning disabilities, delayed growth Caused by the same gene as DMD, resulting in similar symptoms (although less severe) Weakness of all muscle types and delayed relaxation of muscles after contraction
Symptoms
Face, neck, arms, hands, hips, and lower legs
Upper part of legs and arms
Upper part of legs and arms
Body part showing weakness first
Slow progression but very severe: leads to decreased life span
Slow progression and less severe
8 in 100,000 Males and females are equally affected
Slow progression but very severe: leads to decreased life span
Progression and severity
3–4 in 100,000 Males
14 in 100,000 Males
Prevalence Mostly affects
Chakraborty et al. (2016), Meola (2020), Garcia-Puga et al. (2022), Soltanzadeh (2022)
Bradley et al. (1978), Angelini et al. (2019), Sheikh and Yokota (2020), Salari et al. (2022), Ripolone et al. (2022)
McDonald et al. (2002), Yiu and Kornberg (2015), Duan et al. (2021a), Markati et al. (2022)
References
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Limb girdle muscular dystrophy (LGMD)
Type of MD (short form)
Autosomal dominant/ recessive MYOT LMNA CAV3 DES DNAJB6 TNPO3 HNRPDL LGMD1H CAPN3 DYSF LGM2D (C-F) TCAP TRIM32 FKRP TTN POMT1 ANO5 FKTN POMT2 POMGnT1 DAG1 PLEC1 TRAPPC11 GMPPB ISPD GAA LIMS2/ PINCH2
Inheritance Gene involved Gene location
MYOT Lamin A/C Caveolin-3 Desmin DnaJ homolog, subfamily B, member 6 TNPO3 HNRPDL Unknown Calpain-3 Dysferlin sarcoglycan (D)α, (E) β, (C)γ, (F)Δ Telethonin (Titin-cap) Tripartite motif containing 32 Fukutin-related protein Titin (LGMD2J) MDDGC1 Anoctamins Fukutin O-Mannosyl tranferase Protein O-linked-mannose beta-1,2-Nacetylglucosaminyltransferase 1 Dystroglycan Plectin Transport protein particle complex 11 GDP-mannose pyrophosphorylase Isoprenoid synthase Acid alpha-glucosidase LIM and senescent cell antigen-like-containing domain protein 2
Deficient protein Late childhoodmiddle age
Onset of phenotype Weakness and wasting of muscles affecting shoulder girdle and pelvic girdle first
Symptoms Pelvic girdle
Body part showing weakness first 2 in 100,000 Males and females are equally affected
Prevalence Mostly affects Slow progression and less severe and death in these cases are usually due to other related problems like heart issues, etc.
Progression and severity Nigro (2003), Godfrey et al. (2006), Clement et al. (2008), Locke et al. (2009), Mercuri et al. (2009), Bisceglia et al. (2010), Rosales et al. (2010), Sarparanta et al. (2010), Reilich et al. (2011), Stensland et al. (2011), Raducu et al. (2012), Tian et al. (2012), Peterle et al. (2013), Nigro and Savarese (2014), Saredi et al. (2014), Vieira et al. (2014), Hernandez-Lain et al. (2016), Oestergaard et al. (2016), Zhong et al. (2017), Liewluck and Milone (2018), Taghizadeh et al. (2019), Maggi et al. (2021), Pathak et al. (2021), Costa et al. (2020), Findlay et al. (2022), Ohsawa et al. (2022), Johnson and Statland (2022), Nikhanj (2022), Vincenzo et al. (2022)
References
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Autosomal (dominant/ recessive) DUX4 SMCHD1
Autosomal recessive POMT1/ POMT2, POMGnT LARGE FKRP FCMD Fukutin
Autosomal (dominant/ recessive) DES DYS GNE TTN MYH7 ZASP Myotillin Nebulin MATR3
Facioscapulohumeral muscular dystrophy (FSHD)
Congenital muscular dystrophy (CMD)
Distal muscular dystrophy (DMD)
Type of MD (short form)
Inheritance Gene involved Gene location
Birth
Laminin α2 (MDC1A) (MDC1B) Fukutin Protein-Omannosyltransferase 1 Protein O-linked mannose β-1,2-Nacetylglucosaminyltransferase LARGE [putative glycosyltransferase] FKRP (Fukuyama CMD) Fukutin Desmin Dysferlin 2-Epimerase Titin Beta myosin PDZ domain-containing protein Myotilin Nebulin Matrin-3 Late adolescence 40–60 years
Childhood– early teen years
Double homeobox 4(FSHD1) Double homeobox 4, structural maintenance of chromosomes flexible hinge domain containing 1 (FSHD2)
Deficient protein
Onset of phenotype
Weakness and wasting of muscles of the hands, forearms, and lower legs
General muscle weakness and joint deformities
Weakness of facial muscles, wasting of shoulders, and upper arms
Symptoms
Feet, hands, lower legs and lower arms
Neck, upper arms, upper legs, and lungs
Face, shoulders, and upper arms
Body part showing weakness first
1 in 100,000 Males and females are equally affected
1 in 100,000 Males and females are equally affected
4 in 100,000 Males and females are equally affected
Prevalence Mostly affects
Slow progression and less severe: rarely leads to total incapacity
Slow progression and less severe: patient even lives for decades after the onset of the disease Slow progression but severe: shortens life span
Progression and severity
Muelas et al. (2010), Amato and Griggs (2011), Barresi et al. (2012), Udd (2014), Yamashita et al. (2015), Olive et al. (2016), Steiner et al. (2018), Udd and Hackman (2020), Spadafora et al. (2022)
Messina et al. (2010), Clarke et al. (2011), Bonnemann et al. (2014), Sparks (2015), Falsaperla et al. (2016), Ishigaki et al. (2018), Saito (2019), Amiji et al. (2019), Endo (2019), Arreguin and Colognato (2020), Awano et al. (2021), Zambon and Muntoni (2021), Jung and Nagiel (2024), Cavallina et al. (2023)
Sacconi et al. (2015), Klimov (2017), Statland (2020)
References
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Autosomal dominant PABPN1 14q11.2
EMD, LMN, SYNE1, SYNE2, FHL1, TMEM43
OPMD
EDMD
Type of MD (short form)
Inheritance Gene involved Gene location
Emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, LUMA
Poly-A-binding protein 2
Deficient protein
Childhood– early adolescence
40–70 years
Onset of phenotype Weakening of muscles of eyelids and throat causing inability to swallow and severe weight loss due to improper food intake Weakness and wasting of shoulders, upper arm, and shin muscles Joint deformities are also common in EDMD
Symptoms
Arms, legs, heart, and joints
Shoulders, upper legs, and hips
Body part showing weakness first
1 in 100,000 Males
1 in 100,000 Males and females are equally affected
Prevalence Mostly affects
Slow progression and less severe
Slow progression and less severe
Progression and severity
Kelkar et al. (2015), Brull et al. (2018), Heller et al. (2020)
Trollet et al. (2020)
References
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which would cause dysphagia. Due to their influence on the ligaments surrounding the spine and the muscles at the back of the neck, the patient might experience a fixed extended position of the neck. The beginning of skeletal muscle weakness is preceded by cardiac problems such as rapid ventricular and atrial heart rhythms, lack of atrial activity, and cardiac muscle disorder. Detailed list of various muscular dystrophies is summarized in Table 7.1.
7.3 Cellular and Molecular Mechanisms Underlying Muscular Dystrophy The patient’s neck may become stuck in an extended posture as a result of their impact on the paraspinal ligaments and posterior cervical musculature. The neck structure may change as a result of the cervical spine stiffness, which would cause dysphagia. The beginning of skeletal muscle weakness is preceded by cardiac problems such as atrial tachyarrhythmias, atrial standstill, ventricular tachyarrhythmias, and cardiomyopathy. Skeletal muscle fibers’ structural integrity is maintained by this gene, and without the protein dystrophin, the muscle fibers become brittle and more vulnerable to injury, resulting in muscular weakening and wasting. The specific cellular and molecular processes behind muscular dystrophy are explored in this section, with an emphasis on the function of the dystrophin gene.
7.3.1 The Skeletal Muscle Structure Skeletal muscles are a crucial part of the body and participate in a range of fundamental functions, encompassing breathing, eating, communicating, grasping, and movement. Additionally, they aid in thermogenesis, the creation of energy during hunger, the storage of amino acids for protein synthesis, and maintaining good posture (Pozefsky et al. 1976; Feldman 2016; Periasamy et al. 2017; Sylos-Labini et al. 2017; Kamei et al. 2020). About 650 skeletal muscles, which make up 40–50% of the weight of the human body, are multi-fibrous, multi-nucleated powerhouses that contract and expand to create desired motions (Frontera and Ochala 2015). During embryogenesis, mononucleated muscle precursor cells fuse to form skeletal muscle fibers (myofibers). After birth, a muscle stem cell niche known as satellite cells settles in the region between the myofiber and the basal lamina. These cells join with myofibers to lengthen and stimulate growth, and participate in the healing of an injury (Buckingham et al. 2003; Yin et al. 2013). An individual skeletal-muscle cell also known as a muscle fiber, myofiber, or myocyte consists of several nuclei formed by the fusion of myoblasts. Hundreds or thousands of such muscle fibers (myofibers) are bundled together to make up an individual skeletal muscle (Fig. 7.1a). Less than the diameter of a human hair, these are long, cylinder-shaped structures that are connected by a plasma membrane (the sarcolemma) and an
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Fig. 7.1 Skeletal muscle and sarcomere; structural overview. (a) Schematic illustration of the skeletal muscle structure, depicting fascicles, myofibers, and myofibrils enveloped by the corresponding connective tissue layers, including epimysium, perimysium, and endomysium. The nuclei are located towards the periphery of the myofiber, and the muscle is connected to the bone via a tendon. (b) Schematic diagram demonstrating the arrangement of the principal cytoskeletal and regulatory proteins in the sarcomere, which are critical for muscle contraction. Thick filaments consist of myosin and corresponding regulatory proteins, whereas thin filaments consist of actin and regulatory proteins. The positioning of two regulatory proteins that promote muscle contraction, tropomyosin and titin, is also indicated
overlaying basal lamina. When arranged into bundles, or fascicles, they form the muscle. The sarcolemma functions as both a physical barrier between the inside of the muscle cell and the outside world. The structure of skeletal muscle has been extensively studied using electron microscopy and X-ray diffraction, which have provided detailed insights into the organization of the muscle (Luther and Squire 1980, 2014; Ma et al. 2019). Skeletal muscle contraction is generated by the sarcomere, the primary structural unit in the myofibril. Composed of a linear array of cytoskeletal and regulatory proteins, the sarcomere includes alternating thin actin filaments, thick myosin filaments, and associated structural and regulatory proteins such as tropomyosin, troponin, titin, and nebulin (Chal and Pourquie 2017; Henderson et al. 2017). The sarcomere’s striated appearance is due to the structured organization of myofilaments, with each
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sarcomere differentiated into various zones that include the Z-line which anchors the thin actin filaments at the sarcomere border, the M-line, which is the myosinrich center, the I-band, composed of slender filaments, and H-zone which spans both sides of the M-line and consists of thick filaments (Fig. 7.1b). The A-band spans through the H-zone and consists of both thick and thin filaments, giving it a dark appearance.
7.3.2 Neuro-Muscular Coordination for Muscle Contraction Neurons called motor neurons initiate muscle contractions. At the neuromuscular junction, where the nervous system sends instructions to the muscle to contract, they innervate muscle fibers. The liberation of calcium stored in the sarcoplasmic reticulum at the fiber is induced by the nerve impulse upon its arrival at the neuromuscular junction. The protein troponin-C is subsequently bound by the calcium ions that have been released, resulting in a conformational shift that pushes the protein tropomyosin out of the way and reveals the myosin-binding site on the actin filament. The myosin head then binds to the exposed site on the actin filament, forming a cross-bridge. Muscle contraction derives its fuel from the hydrolysis of ATP, which is catalyzed by the enzyme myosin ATPase, powering the sliding of myosin over the actin that causes the sarcomere shortening. As the sarcomere shortens, the gap within the Z-line and M-line, H-zone, and I-band reduces while the A-band remains the same. This shortening of the sarcomere is what leads to muscle contraction (Huxley 1969; Huxley and Kress 1985). The muscle is covered in connective tissues that provide structural support, such as endomysium, perimysium, and epimysium (Rowe 1981). Each myofiber is covered in endomysium, whereas the fascicles (bunches of myofibers) are surrounded by the perimysium. The outermost layer encasing the whole muscle is called the epimysium. The cytoskeletal components of the costamere protein complex, which are made up of the Z-line and M-line that attach the functional contractile unit to the cell membrane or sarcolemma, are essential for the healthy operation of muscle cells. These connections enable the muscle to contract efficiently and transmit the resulting forces to the extracellular matrix (ECM) to prevent damage to the sarcolemma (Pardo et al. 1983; Jaka et al. 2015). The precise structure and function of costameres, which synchronize the movement of myofibrils during contraction and guarantee that they cooperate to produce force, have been uncovered via research on people, muscle cell lines, and numerous model species. The myotendinous junction, which connects muscles and bones, transmits the muscle’s contractile power to the tendon, causing that particular bone to move (Rack and Westbury 1984; Rack et al. 1983; Maganaris 2002). MD results from the errors in skeletal muscle architecture and signaling, underlining the critical function of skeletal muscle’s intricate architecture.
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7.3.3 Dystrophin Gene (DMD) The gene responsible for encoding dystrophin, a protein found in skeletal muscles, is called DMD and is situated on the X chromosome’s short arm (Xp21 region). It comprises roughly 2.5 million base pairs, having 79 axons in humans (Hoffman et al. 1987; Koenig et al. 1987). The DMD gene mutations cause various muscle degenerative disorders known as dystrophinopathies, including DMD, which was initially reported by Edward Meryon in 1852 and named after Guillaume–Benjamin–Amand Duchenne who provided a thorough explanation of medical condition in 13 boys affected by DMD (Emery and Emery 1993; Emery 2002; Rondot 2005). The DMD gene is transcribed in various tissues into different mRNA isoforms. A prominent dystrophin isoform (Dp427), a 427 kDa protein, is transcribed from a 14 kb mRNA in the skeletal muscles and heart (Monaco et al. 1988; Blake et al. 2002). Expression of the full-length mRNA is controlled by three tissue-specific promoters: DNp427-M in muscles, DNp427-B in the brain (CA region of hippocampus and cortex), and DNp427-P in cerebellar Purkinje cells (Blake et al. 2002). Shorter truncated transcripts are produced by internal promoters that encode truncated C-terminal isoform: Dp260-R in the retina, DNp140-B and DNp40 in the brain, DNP116-S in the Schwann cells, and DNP71-G, generally found in multiple organs (Fig. 7.2a) (Wersinger et al. 2011; Romo-Yanez et al. 2020; Kawaguchi et al. 2018). Dystrophin, a cytoskeletal protein, comprises of tetra-domains: an initial actin-binding domain (ABD) at the N-terminal, the terminal domain (CTD), spanning in between a core central rod-like domain, and a cysteine-rich domain (CR).
Fig. 7.2 Schematic showing the DMD gene and the muscle-specific dystrophin protein. (a) The DMD gene spans 2.5 million base pairs and contains 79 exons. Seven tissue-specific promoters are shown, including DNp427-M (for muscles), -B (for the brain; specifically, the CA region of hippocampus and cortex), and -P (for cerebellar Purkinje cells). (b) The muscle-specific dystrophin protein is 427 kDa and consists of four main domains: an N-terminal actin-binding domain (ABD), 24 rod-shaped spectrin-like repeats (R1–24), four proline-rich hinge regions (H), cysteine-rich (CR) domain, and a C-terminal domain (CTD) encoded by exons 1–8, exons 8–64, exons 64–70, and exons 71–79, respectively
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Central rod-like core region comprises around 24 spectrin-like coiled coil repeating units (R1–R24) that are alpha-helical, and four hinge segments (H1–H4) rich in proline (Koenig and Kunkel 1990) (Fig. 7.2b).
7.3.4 Dystrophin Protein and Dystrophin-Associated Protein Complex (DAPC) Dystrophin is a long rod-shaped, subsarcolemmal spectrin-like protein that is vital for the functioning of muscles (Zubrzycka-Gaarn et al. 1988). It is a major component of the costamere, where the N-terminal domain and spectrin-like repeats R11–15 bind to the thin actin filaments. The dystrophin’s CR and the CTD domains interact with a transmembrane protein β-dystroglycan, which binds to laminin via α-dystroglycan. Dystrophin also interacts with the transmembrane via two regions situated at R1–3 and R10–12 (Fig. 7.3) (Amann et al. 1998; Muthu et al. 2012; Duan et al. 2021a; Starosta and Konieczny 2021). Spectrin-like repeats of dystrophin, R8 and 9, bind MARK2 (PAR1b), while R4–15 and R20–23 bind to microtubules, which in turn connect to ankyrin-B which also binds with dystrophin (Prins et al. 2009). Additionally, syntrophins or dystrobrevin, which are known to attract sodium channels, and a cell signaling molecule nitric oxide synthase that is neuronal (nNOS), are known to bind to the C-terminal of dystrophin. Dystrophin interacts directly or indirectly within muscle with the membrane, cytoskeletal elements (including actin, intermediate filaments, microtubules, and related structural proteins), signaling or scaffolding proteins, channels, along with various other protein components (Ervasti and Campbell 1991). The dystrophin-associated protein complex (DAPC) is made up of dystrophin and its interacting protein partners. It connects the cytoskeleton to the extracellular matrix, providing a buffer to protect sarcolemma from contractile forces. Originally perceived as a structural assembly safeguarding the sarcolemma against physical harm, the DPC functions as a framework for multiple signaling proteins and ion channel function (Fong et al. 1990; Franco Jr and Lansman 1990; Sander et al. 2000). DAPC also regulates calcium-dependent potassium channel localization at the neuromuscular junction (NMJ) (Sancar et al. 2011). At the NMJ, dystroglycan is involved in the aggregation of acetylcholine receptors (AChRs) via interactions of α-dystroglycan with agrin and perlecan, and β-dystroglycan with rapsyn. Muscular dystrophies are a category of hereditary illnesses in which recurrent episodes of injury induce wasting and fibrous tissue formation and finally degeneration of muscles. Muscular dystrophies are caused by dystrophin absence or decreased expression, or by several of the DPC components (Sweeney and Barton 2000).
7.3.5 Genetics and Mutations in the Human Dystrophin Gene Dystrophinopathies are MDs linked to the X chromosome, arising due to mutations in the dystrophin gene. These disorders include various dystrophies already discussed in Sect. 7.1 which include severe DMD, BMD, and DMD-associated
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Fig. 7.3 Schematic diagram of the dystrophin-associated protein complex (DAPC) showing its components and their interactions. The N-terminal domain (NTD) and spectrin-like repeats R11–15 bind to F-actin filaments, while R8 and R9 bind to MARK2. R20–23 anchor microtubules and R1–3 and R10–12 can directly bind to the sarcolemma. The C-terminal domain (CTD) interacts with cytosolic proteins such as syntrophins or dystrobrevin, which engage with sodium channels, caveolin-3, and other signaling molecules (e.g., nNOS, neuronal nitric oxide synthase). The cysteine-rich (CR) domain binds to β-dystroglycan, which interacts with α-dystroglycan, facilitating force transfer during muscle contraction. At the neuromuscular junction (NMJ), acetylcholine receptors (AChRs) cluster due to interactions between α-dystroglycan and agrin/perlecan, and β-dystroglycan and rapsyn. At the sarcolemma, β-dystroglycan also interacts with and stabilizes the sarcoglycan and the sarcospan complex. The proteoglycan biglycan anchors to the sarcoglycan and dystroglycan
cardiomyopathy (DCM), as well as some milder versions causing spasms accompanied by myoglobinuria as well as increased CK levels. DMD that stands as the predominant MD occurs due to the number of mutations in the gene DMD (Fig. 7.4). To date, more than 7000 mutations have been documented, with large deletions being the most common (~60–79%), followed by duplications (~7–20%). Deletions are typically clustered around 45–55 exons (~47% of cases) and 3–9 exons (~7% of cases), while duplications are most common in exon 2 (Flanigan et al. 2009). Small lesions such as point mutations, insertions, and small deletions account for approximately 5–14% of instances (Aartsma-Rus et al. 2006; Bladen et al. 2015; Duan et al.
Fig. 7.4 Distribution of mutations leading to DMD. (a) Schematic representation of the most common mutations in the dystrophin gene, highlighting the location of deletions (red -), duplications (green -), nonsense mutations (gray x), and small lesions/point mutations (blue *). The most common deletions occur in clusters around exons 45–55 (~47% of cases) and 3–9 (~7% of cases), while duplications are most frequent in exon 2. (b) The median frequency of each mutation type is shown, with deletions being the most prevalent (~60–79% of cases) followed by duplications (~7–20%). (c) Comparison of full-length dystrophin and mutated dystrophin resulting from different mutations
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2021a; Gambetta et al. 2022; Viggiano et al. 2023). Spontaneous mutations are common in DMD due to germline mutations, with a rate of approximately 1 in 10,000 sperm or eggs due to the enormous length of the gene DMD. Translocations, which are rare but have been observed in men and women (Nevin et al. 1986; Duan et al. 2021a), can also cause DMD. The reading-frame principle mostly distinguishes between DMD and BMD (Monaco et al. 1988). Premature stop codons are produced due to frame-shift mutations that affect the coding sequence orientation of the dystrophin gene. This interferes with the translation of the dystrophin protein, causing it to be altered, inactive, or truncated. Most commonly, these mutations result in DMD, which affects people with little to no functioning dystrophin protein. On the other hand, in-frame mutations that maintain the reading frame may result in a dystrophin protein that is incomplete but still partially functional and still has its C-terminal domain. Typically, these mutations lead to BMD, a milder type of muscular dystrophy in which affected people have some functioning dystrophin protein but not enough to stop long-term muscle degradation (Hoffman et al. 1987; Magri et al. 2011).
7.3.6 Consequences of Dystrophin Mutation Dystrophin protein is either absent or produced in a shortened form that cannot attach to a transmembrane protein, resulting in an acute type of DMD. BMD is brought on by mutations that result in partially functioning dystrophin with an intact C-terminal and actin-binding capabilities. Insufficient dystrophin also hinders the development of the DAPC assembly. As a result, mechanical stability and cell signaling are impacted by the loss of the link between intracellular actin and external proteins. The loss of DAPC can have a number of effects, including the initiation of non-exclusive pathogenic cascades that can cause muscle degeneration and delayed muscle regeneration.
7.3.6.1 Mechanical Instability and Sarcolemma Disintegration Sarcolemma damage is observed in DMD patients using electron microscopic studies, referred to as delta lesions (Mokri and Engel 1975; Wakayama et al. 1983; Pestronk et al. 1982). The DAPC is fashioned as the mechanical framework that protects the sarcolemma’s integrity and serves as a conduit for the contractile forces produced by muscle flexion and extension. Scarcity of dystrophin makes the sarcolemma susceptible to mechanical injury because it cannot withstand the stress brought on by muscular action (Petrof et al. 1993; Dudley et al. 2006; Duan et al. 2021a). Creatine kinase, a muscle enzyme, is found in higher concentrations in the serum as a result of sarcolemma breakdown, which makes it more porous. Following mechanical stress brought on by repeated activity in the dystrophic muscle, which damages the transmembrane and related components, the leakage is further amplified (Lovering and De Deyne 2004; Lovering et al. 2007; Houang et al. 2015), and measured by studying leakage of various large proteins such as albumin in humans and animal models (Petrof et al. 1993; Matsuda et al. 1995). Mechanical
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stress-induced damage is also prominently seen in the diaphragm, the largest muscle involved in respiration (Stedman et al. 1991). Sarcolemma stabilization based on copolymers, extracellular matrix linking, and gene therapy to partially reinstate sarcolemma components or related cytoskeletal elements, all dramatically slow down the course of muscular dystrophy in a variety of model species (Burkin et al. 2001, 2005; Duan 2018, Duan et al. 2021a; Houang et al. 2015). Sarcolemma destabilization also is influenced due to mechanical forces, aberrant cell signaling, and oxidative stress.
7.3.6.2 Abnormal nNOS-Mediated Cell Signaling Neuronal nitric oxide synthase (nNOS) is a cell signaling molecule that binds to dystrophin (R16 and R17 domain) and DAPC that anchors it to the sarcolemma (Lai et al. 2009). As the skeletal muscle contracts, NO generated by nNOS is released into the area’s blood arteries. Guanosine monophosphate, a second messenger that encourages vasodilation, is produced as a result of it (Kukovetz et al. 1987; Rahimov and Kunkel 2013). Due to nNOS mislocalization brought on by dystrophin deficiency, NO generation at the transmembrane is decreased. When NO-mediated vasodilation is absent, functional muscular ischemia is caused during muscle contraction, and reperfusion occurs during muscle relaxation (Thomas et al. 1998; Dudley et al. 2006; Sander et al. 2000). In DMD patients, a brief 10-min period of muscular ischemia followed by a minute of reperfusion resulted in higher blood creatine kinase levels, demonstrating that this procedure similarly causes sarcolemma destabilization (Dudley et al. 2006). Treatment with phosphodiesterase inhibitors and gene therapy using mini-dystrophin including nNOS binding domains (R16 and R17) minimize ischemia during exercise in mice and canine DMD models (Kobayashi et al. 2008; Lai et al. 2009; Kodippili et al. 2018; Patel et al. 2018). Both dramatically improve cGMP signaling by inhibiting phosphodiesterase-induced cGMP degradation and sarcolemmal nNOS localization, respectively. According to Dudley et al. (2006), NO also regulates some elements of muscle metabolism and prevents leukocyte adhesion. Nitric oxide facilitates cell–cell communication and has a variety of functions in the muscle. NO controls inflammation, proteolysis, apoptosis, muscular force, synapse formation and function, and muscle metabolism in addition to its involvement in vasodilation (Reid 1998; Tidball and Wehling- Henricks 2007). 7.3.6.3 Oxidative Imbalance and Harm from Reactive Radicals Both in DMD patients and animal models, oxidative imbalance and harm from reactive radicals is seen in the dystrophic muscles. Dystrophic muscles exhibit elevated levels of lipid peroxidation, protein carbonyls, and other indicators of oxidative stress caused by the buildup of reactive oxidation species (ROS) produced during cell metabolism (Tidball and Wehling-Henricks 2007; Abdel et al. 2007; Choi et al. 2016; Duan et al. 2021a). When Rac1, a microtubule-associated protein, activates the NOX2 enzyme during muscular extension, it creates reactive oxygen species (Prosser et al. 2011; Kim et al. 2013; Duan et al. 2021a). The spectrin-like repetitions R21–24 on dystrophin serve as an anchor for microtubules, and dystrophin
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loss results in disorganized and condensed microtubules, which boost Rac1- mediated ROS generation (Khairallah et al. 2012). The lowering of NO at the transmembrane caused by the loss of the nNOS-dystrophin connection has an impact on homeostasis as well (Dudley et al. 2006; Tidball and Wehling-Henricks 2007). Reactive nitrogen species (RNS), which are produced by mislocalized nNOS in the cytosol and alter muscular force, are another issue (Li et al. 2011). Due to inflammatory cell invasion and mitochondrial malfunction, DMD muscle also generates more free radicals. Pathogenesis in the dystrophic muscle is aided by diminished antioxidative compensatory systems. While HO-1 expression and several antioxidant medications have demonstrated the potential in enhancing muscle pathology and lowering cell death (Millay et al. 2008; Nakae et al. 2008; Chan et al. 2016; Vitiello et al. 2018; Petrillo et al. 2017; Nelson et al. 2020; Duelen et al. 2022). Additional investigation is required to uncover the therapeutic possibilities and the fundamental mechanisms related to oxidative stress in DMD.
7.3.6.4 Chronic Inflammation Chronic inflammation is a key consequence of dystrophin deficiency. When dystrophin is lost, the muscle membrane breaks down, allowing different proteins to seep into the extracellular matrix. With the help of soluble cytokines, the complement system, and non-specific immune cells including macrophages, neutrophils, and monocytes, this causes an innate immune response in dystrophic muscles. Numerous processes, including the release of damage-associated molecular patterns like ROS, heat shock proteins, and high mobility box-1 protein from the injured muscle cells, are involved in mediating this immunological response. These chemicals cause the sarcolemma’s Toll-like receptors (TLRs) to become active, which causes proinflammatory proteins and cytokines to be expressed and secreted (Henriques-Pons et al. 2014). The inflammatory response and apoptosis (programmed cell death) of the injured tissue are made worse by the immune cells that invade the damaged muscle (Starosta and Konieczny 2021). Dystrophic animals have been demonstrated to exhibit less disease when TLRs or MyD88, an adaptor protein activated by TLR and the proinflammatory cytokine IL-1 receptor, are inhibited (Gallot et al. 2018). This shows that focusing on the immune system may be a promising therapy strategy for DMD. The course of muscle fibrosis and degeneration in DMD is significantly influenced by chronic inflammation, which also contributes to the emergence of the disease’s numerous clinical symptoms. For instance, muscular weakness, contractures, joint deformities, as well as respiratory and heart problems can all be brought on by chronic inflammation and fibrosis. Therefore, lowering chronic inflammation in DMD may be a key tactic to enhance the therapeutic results of individuals with this crippling condition. 7.3.6.5 Dysregulation of Intracellular Calcium Several entry points, such as sodium-calcium exchange transporter, mechanosensitive ion channels, store-operated, receptor-mediated and voltage-gated calcium channels, calcium-exporting ATPase on the cell membrane, are used by the loss of dystrophin to cause an increased influx of calcium during myofibril contraction
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(Turner et al. 1988; Allen et al. 2016). The majority of these channels are connected to DAPC through calmodulin, and calcium entry may be facilitated by a disintegrating sarcolemma. The sarcoplasmic reticulum releases calcium through ryanodine receptor channels during myofibril contraction, and SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) pumps are active when the muscle relaxes. Lack of dystrophin promotes the generation of free radicals, which can cause the ryanodine receptor to be nitrosylated and phosphorylated. Due to this alteration, the receptor remains permanently open, allowing calcium ions to flow out (Bellinger et al. 2009; Kyrychenko et al. 2013; Duan et al. 2021a). Although ryanodine receptor stabilizers and transgenic overexpression of SERCA reduced pathology, calcium channel blockers did not alleviate pathology in a murine MD model (Bellinger et al. 2009; Phillips and Quinlivan 2008; Capogrosso et al. 2018). The overdose of calcium can harm muscles by triggering a number of calcium- dependent processes. For example, it can lead to the activation of phospholipase A2, which damages the sarcolemma, and the cleavage of dysferlin, a critical protein involved in the membrane repair mechanism of muscle cells (Lindahl et al. 1995; Gailly et al. 2007; Han and Campbell 2007; Houang et al. 2015). Furthermore, higher calcium levels can result in mitochondrial malfunction, which lowers ATP synthesis and raises the formation of reactive oxygen species, which leak into the sarcoplasm as a result of increased mitochondrial porosity (Kyrychenko et al. 2013). Calcium overload can also induce muscle degeneration through mitochondrial- dependent cell death (Kyrychenko et al. 2013) and disrupt calcium-dependent calmodulin and calcineurin pathways in DMD muscles (Niebroj-Dobosz et al. 1989). Recent research indicates that high calcium levels may also impact muscle development and regeneration and that cycling calcium to control its levels enhances muscle differentiation in dystrophic animals (Niranjan et al. 2019). Together, the absence of dystrophin and the ensuing calcium excess can have a variety of negative consequences on muscular function, as well as cause muscle aging and hinder muscle recovery.
7.3.6.6 Disrupted Muscle Repair Dystrophic muscles are unable to constantly repair themselves. It was previously believed that the exhaustion of the satellite cell reservoir was caused by repeated attempts to restore the weak muscle in DMD. Recent investigations, however, have shown that satellite cells have high levels of dystrophin expression, which controls their cell polarity, division, and commitment (Dumont et al. 2015; Chang et al. 2018). To promote spindle orientation and centrosome amplification, dystrophin asymmetrically binds to the transmembrane microtubule affinity regulating kinase 2 (MARK2) (DPAC protein) (Starosta and Konieczny 2021) for asymmetric satellite cell division. Another DPAC protein, β1-syntrophin, interacts with p38γ (MAPK12) to induce myogenic differentiation. Loss of 1-syntrophin due to dystrophin deficiency affects p38 (MAPK12) signaling, which affects Carm1 nuclear transport. By methylating Pax7, Carm1 regulates gene expression in asymmetric satellite cell division, which in turn causes the production of Myf5, which is necessary for myogenic commitment and the development of polarity (Chen et al. 2002;
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Saber and Rudnicki 2022). Additionally, carm1 activates genes associated with lysosomes and autophagy. Therefore, dystrophin deficiency-mediated loss of carm1 nuclear transportation may result in aberrant autophagy in DMD muscles, which includes an inability to clean damaged mitochondria. This would increase free radical generation and satellite cell senescence (Garcia-Prat et al. 2016). Even when asymmetrical division is restricted, elevated amounts of satellite cell pools are seen in DMD muscles. This is likely because of aberrant symmetric division. Pax7 + / Myf5 + satellite cell pool, however, gets smaller with time. ROS and numerous other elements also contribute to this reduction (Lu et al. 2014; Starosta and Konieczny 2021). Thus, dystrophin deficiency/DPAC disassembly leads to impaired regeneration due to the impaired satellite cell divisions and myogenic commitment. More work is needed to explore the signaling that leads to these alterations and the consequences of the direct and indirect impact of dystrophin deficiency in the DMD muscle.
7.4 Important Diagnostic Approaches for Muscular Dystrophies Various diagnostic approaches have been developed which include testing at the genetic level, enzymatic levels, protein level, and muscle biopsy. The cornerstone of diagnosis is molecular genetic analysis. The detection of deletions and duplications (copy number variations) in MDs, which are inherited genetic illnesses affecting several genes, can be done using multiplex ligation- dependent probe amplification (MLPA) or high-resolution microarray technology (Laing et al. 2011). The protein that results from a gene can also be utilized to make diagnoses. For instance, immunostaining and/or Western blot examination can demonstrate dystrophin’s absence or almost complete absence, which is indicative of DMD (Hoffman et al. 1988). Creatine kinase (CK) levels in the serum are measured during an enzyme test. Prior to reaching 5 years of age, serum CK levels in DMD display notably heightened values, typically exceeding the upper limit of normal by at least 10- to 20-folds (usually around 50- to 200-folds) (Darras et al. 2014). Although biopsy is a crucial diagnostic method, it is typically not clinically necessary if genetic testing is conclusive. It is performed solely when there are symptoms or when genetic testing yields false negatives. Typical features observed in muscle histology include tissue deterioration and death, accompanied by infiltration of mononuclear cells. Additionally, connective and adipose tissues substitute a sizable amount of muscle (Darras et al. 2014). With the development of science, today’s physical aids, such as sensors and artificial intelligence (AI), are used to maintain posture and gauge the severity of the condition. This is one of the major advancements in MD diagnostic methods (Panero et al. 2023; Ricotti et al. 2023).
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7.5 Various Treatment Strategies for MD While no therapy exists for MD, treatment for a few forms could extend the longevity. Various treatment modalities, including as medication, physical and occupational therapy, surgery, and other treatments, have been employed to date. Current clinical studies are investigating novel remedies.
7.5.1 Medications Prednisone and deflazacort (Emflaza), two drugs that include corticosteroids, can boost muscle power and decelerate the evolution of several MDs. Nevertheless, prolonged usage of these drugs could potentially lead to obesity, bone fragility, and heightened susceptibility to fractures. Eteplirsen (Exondys 51), the first treatment to be authorized (in 2016), and golodirsen (Vyondys 53), approved in 2019, are a couple of significant FDA-approved medications for DMD. In certain circumstances, heart medicines including beta-blockers or angiotensin-converting enzyme antagonists are also employed (Lim et al. 2017).
7.5.2 Therapies Various therapeutic approaches for MD patients and supportive tools can enhance the well-being and lifespan (Henschke 2012). Range-of-motion and stretching exercises: Muscular dystrophy can restrict the flexibility and mobility of joints. Limbs often draw inward and become fixed in that position. Range-of-motion exercises can help maintain joint flexibility (Morris et al. 2020). Exercise: Gentle cardio-vascular workouts such as walking and swimming support sustaining physical strength, overall well-being, and mobility. Furthermore, certain types of strength-building exercises may offer advantages. Nevertheless, before engaging in any workout, it is crucial to speak with your doctor (Grange and Call 2007). Braces and mobility aids: Braces can deter the progression of contractures and enhance mobility and functionality by providing support to weakened muscles (Do 2002). Canes, walkers, wheelchairs, etc. could help maintain mobility and independence (Do 2002; Blokhuis et al. 2021). Breathing assistance: As respiratory muscles weaken, a sleep apnea device might help improve oxygen delivery during the night. Some people with severe muscular dystrophy need to use a ventilator (Mhandire et al. 2022).
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7.5.3 Surgery Surgery might be needed to correct contractures or a spinal curvature that could eventually make breathing more difficult. Heart function may be improved with a pacemaker or other cardiac device (Sussman 2002; Eagle et al. 2007; Muenster et al. 2012).
7.5.4 Nano-technological Approaches for MD As the cure for MD is yet to be established, it is an area of ongoing research. The strategies aiming at patient care for MD can focus on either addressing the underlying genetic defect or treating the resulting muscle loss (Lim and Yokota 2021); however, traditional treatment strategies lean heavily towards symptom management and slowing the disease progression (Radley et al. 2007). Nanotechnology is at the cutting edge of widely spreading and highly evolving sciences can lead to enhancement in therapeutic strategies following either of these directions. Nanotechnology employs various types of materials whose functional lengths fall within the nanoscale (1–100 nm). Researchers have studied materials with unique properties such as size-dependent optical, magnetic, catalytic, and electronic properties, as well as an increased surface area to volume ratio, for use in medicine. This has given rise to the field of nano-medicine. Nano-medicinal approaches have been being used to improve the pharmacokinetic profiles of various drugs by targeting the site of action directly by facilitating membrane transport in cases where traditional drugs simply were not of pragmatic use, or enhancing drug release thus leading to studies involving targeted drug delivery (TDD), blood–brain barrier (BBB) crossing/blood–retina barrier (BRB) crossing and stimulated release, respectively. For MD, in particular, nanotechnology has primarily been used to facilitate drug and oligonucleotide delivery, which can enhance gene therapy approaches and aid in tissue regeneration following muscle loss. Accordingly, we categorize the nano-medical approaches to MD as follows: 1. Targeted delivery of active molecules (drugs/nucleotides/genes therapies) 2. Regenerative medicine/tissue engineering
7.5.4.1 Targeted Drug Delivery and Genes Therapy for MD Treatment Nano-drug delivery primarily targets the drug molecule delivery to the location of interest of action by attaching specific types of recognizing molecules to the nano- vehicles, causing them to bind to and release their load (drug) at the site of action. This approach has been used to enhance the efficacy of drugs and/or limit the side effects of various existing drugs. Researchers have studied liposomes, polymeric nanoparticles, and dendrimers for this purpose to deliver drugs directly to affected muscles, thereby minimizing systemic side effects (Yukihara et al. 2011; Márquez-Miranda et al. 2017). PEGylated nanoliposomes were employed to deliver methylprednisolone hemisuccinate (MPS) to dystrophin-deficient mdx mice (Turjeman et al. 2019).
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Researchers compared the efficacy of the nano-drug to that of the traditionally used glucocorticosteroids. The nanoliposomes loaded with the prodrug showed desirable bioactivity and demonstrated lower off-target effects, such as osteoporosis, compared to the control treatment. This was attributed to enhanced drug accumulation in target tissues, lowered serum TGF-β, and reduced diaphragm macrophage infiltration, respectively (Turjeman et al. 2019). Pentamidine can enhance muscle performance in patients with DM1 (Klein et al. 2015), but its use is limited by poor tissue penetration and potentially toxic side effects. Pertinently in a recent study, the researchers developed hyaluronic acid- based nanocarriers to encapsulate pentamidine. Pentamidine-loaded nanocarriers yielded more substantial enhancements in muscle performance than free pentamidine in a mouse model of DM1. The nanocarriers were also shown to accumulate in skeletal muscle tissue, suggesting that they effectively delivered the drug to the target tissue (Repellin et al. 2023). Gene therapy involves the correction of genetic defects so given the very nature of MD, it should be theoretically possible to attack this disease at its source (Mendell et al. 2012). Nanoparticle vehicles can be used to deliver the gene therapy vectors to affected muscles, which could translate to long-term correction of genetic defects. Utilization of nanoparticle-based Cas9 RNP and donor DNA delivery in vivo via local administration decreases fibrous tissue formation and enhances partial muscle performance (Lee et al. 2017; Duan et al. 2021b). Adenoviral vectors successfully deliver encoding CRISPR/Cas9 multiplexes into the DMD muscle fibers (Maggio et al. 2016). Exosomes, which are naturally released from cells and are vital in cell communication, have been investigated for cellular targeting. However, until recently, they were known to possess a limited capacity for encapsulation (O’Loughlin et al. 2012). Hybrid exosomes have been prepared now to overcome this limitation. By incubating exosomes with liposomes, the researchers were able to create fused nanoparticles that effectively enclose substantial plasmids, encompassing CRISPR/ Cas9 expression vectors (Lin et al. 2018). These hybrids were able to successfully transfect mesenchymal stem cells which is very difficult to achieve using liposomes alone. Following this, the CRISPR/Cas9 system is effective in rectifying deletion and point mutations in the dystrophin gene (Happi Mbakam et al. 2022). Furthermore, there is an ongoing investigation into the treatment of duplication mutations (less researched MD). Researchers are also conducting studies on the modification of exon duplications using the CRISPR/Cas9 system in primary myoblasts obtained from a DMD patient (Wang et al. 2022).
7.5.4.2 Nano-regenerative Approaches for MD Treatment In addition to drug delivery, nanotechnology has also been studied for its potential in regenerative therapies for MD. It was demonstrated during the late twentieth century that implanting functional satellite cells into dystrophin-deficient mdx mice could potentially enhance dystrophin-positive muscle cell quantity. Survival of stem cells was, however, of prime concern when it comes to cellular regeneration in MD using stem cells (Maffioletti et al. 2014) and nanoparticles can act as carriers for
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stem cells, protecting them from degradation and enhancing their delivery to affected muscles. Additionally, Au and Ag nanoparticles have been shown to improve the attachment, proliferation, and myoblast cell line differentiation through p38 mitogen-activated protein kinase (MAPK) signaling pathway (Ge et al. 2018). Interleukin-loaded nanoparticles also enhanced muscle performance in murine MD models (Raimondo and Mooney 2021). The dystrophin gene was successfully repaired in DMD patient-derived induced pluripotent stem (iPS) cells using HAC and CRISPR technologies (Jin et al. 2020; Kazuki et al. 2021). Subsequently, the rectified iPS cells underwent differentiation into skeletal muscle but showed only partially restored muscle function, indicating the need for additional strategies to improve dystrophin levels over an extended duration. Scaffold engineering is a research field in itself and primarily focuses on the development of durable, biocompatible, and, at the same time, biodegradable platforms for tissue growth. Nanofiber-based scaffolds could be another promising avenue for post-MD patient care (Wang et al. 2015; Cai et al. 2017; Cheesbrough et al. 2022). Ferric oxide nanoparticles have recently been used to develop smart implants utilizing magnetic actuation to enhance tissue repair. The implant is a scaffold designed using a 3D multilayer method. In an experimental model involving rat nerve defects, there was observed enhancement in remyelination and the emergence of nerve extensions within the regenerated area, along with various other effects, and could also reduce muscle atrophy (Qian et al. 2023). Such research will help in tissue regeneration in patients with muscular dystrophy by providing a new approach to tissue engineering, such as intrinsic magnetic actuation, and contribute to multifunctional regeneration of severe tissue injury, which could be beneficial for patients with muscular dystrophy. Therefore, we can safely say that nanotechnology and nanomedicine certainly demonstrate potential for targeted drug delivery, regenerative therapies, and gene therapy in MD treatment. However, additional investigation is necessary to thoroughly delve into the capabilities of these technologies and to formulate treatments that are both secure and efficacious for individuals with MD.
7.6 Conclusion In conclusion, MD is a group of heritable gradually worsening muscle-wasting disorders that affect millions of individuals worldwide, significantly limiting the quality and quantity of the years of life. This chapter offers an inclusive exploration of diverse types of MDs, encompassing Duchenne MD, Becker MD, Myotonic dystrophy, Limb Girdle MD, Facioscapulohumeral MD, Congenital MD, Distal MD, Oculopharyngeal MD, and Emery-Dreifuss MD. For each type, we have described the specific mutations and the underlying genes, affected muscle types, extent and the onset of degeneration, as well as common symptoms. Additionally, we discussed the cellular and molecular mechanisms underlying MD, focusing on the dystrophin
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gene and its protein products. We describe the skeletal muscle architecture and the role of dystrophin protein and its associated protein complex in maintaining sarcolemmal structural integrity and muscle function. We proceed on to describe the various diagnostic and treatment strategies for MD, with a special focus on an emerging field of nanotechnology-based approaches. The decades of research into MD have given an insight into the genes involved and some of the mechanisms that contribute to disease progression. A mutant gene that induces muscle degeneration can lead to a domino effect where degenerating muscle can influence other signaling pathways and aberrant immune responses. Thus, in some cases, it is difficult to ascertain whether the consequence or phenotype is the direct effect of gene mutation or due to muscle degeneration. Recent advances in multi-omics and artificial intelligence may offer a promising avenue for providing further understanding into an open question regarding the various mechanisms that lead to MD. While current interventions only offer a limited improvement to the quality of life or disease progression, promising research and technological improvement in gene therapy, stem cell therapy, and CRISPR may eventually provide a means to correct the underlying molecular error responsible for MD. Though a cure remains elusive, early diagnosis and intervention can still be valuable in improving the overall quality of life for those affected by the disease. Continued research and worldwide collaboration among scientists, clinicians, and patients will be instrumental in advancing our understanding of MD and developing effective treatments. With the development of cutting-edge technologies, genetic counseling, and intervention of the scientific community, we can make strides in developing cures and improving the quality and quantity of the years of life of those affected by this debilitating disease.
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Viggiano E, Picillo E, Passamano L, Onore ME, Piluso G, Scutifero M, Torella A, Nigro V, Politano L (2023) Spectrum of genetic variants in the dystrophin gene: a single centre retrospective analysis of 750 Duchenne and Becker patients from southern Italy. Genes (Basel) 14(1):214 Vincenzo M, Michelangelo M, Costanza S, Francesca T, Lucia C, Greta A, Anna R, Fulvia B, Adelaide CM, Giovanna L, Elisabetta M (2022) A single mtDNA deletion in association with a LMNA gene new frameshift variant: a case report. J Neuromusc Dis 22:1–6 Vitiello L, Marabita M, Sorato E, Nogara L, Forestan G, Mouly V, Salviati L, Acosta M, Blaauw B, Canton M (2018) Drug repurposing for Duchenne muscular dystrophy: the monoamine oxidase B inhibitor safinamide ameliorates the pathological phenotype in mdx mice and in myogenic cultures from DMD patients. Front Physiol 14(9):1087 Wakayama Y, Bonilla E, Schotland DL (1983) Muscle plasma membrane abnormalities in infants with Duchenne muscular dystrophy. Neurology 33(10):1368–1370 Wang L, Wu Y, Guo B, Ma PX (2015) Nanofiber yarn/hydrogel core–shell scaffolds mimicking native skeletal muscle tissue for guiding 3D myoblast alignment, elongation, and differentiation. ACS Nano 9:9167–9179 Wang DN, Wang ZQ, Jin M, Lin MT, Wang N (2022) CRISPR/Cas9-based genome editing for the modification of multiple duplications that cause Duchenne muscular dystrophy. Gene Ther 29:1–8 Wersinger E, Bordais A, Schwab Y, Sene A, Benard R, Alunni V, Sahel JA, Rendon A, Roux MJ (2011) Reevaluation of dystrophin localization in the mouse retina. Invest Ophthalmol Vis Sci 52(11):7901–7908 Wicklund MP, Kissel JT (2014) The limb-girdle muscular dystrophies. Neurol Clin 32(3):729–749 Wilton-Clark H, Yokota T (2023) Biological and genetic therapies for the treatment of Duchenne muscular dystrophy. Expert Opin Biol Ther 23(1):49–59 Witting N, Duno M, Petri H et al (2013) Anoctamin 5 muscular dystrophy in Denmark: prevalence, genotypes, phenotypes, cardiac findings, and muscle protein expression. J Neurol 260:2084–2093 Wood L, Bassez G, Bleyenheuft C et al (2018) Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease. Orphanet J Rare Dis 13:1–11 Yamashita S, Mori A, Nishida Y, Kurisaki R et al (2015) Clinicopathological features of the first Asian family having vocal cord and pharyngeal weakness with distal myopathy due to a MATR3 mutation. Neuropathol Appl Neurobiol 41(3):91–398 Yin H, Price F, Rudnicki MA (2013) Satellite cells and the muscle stem cell niche. Physiol Rev 93(1):23–67 Yiu EM, Kornberg AJ (2015) Duchenne muscular dystrophy. J Paediatr Child Health 51(8):759–764 Yu H, Chen YC, Liu GL, Wu ZY (2017) A de novo mutation in dystrophin causing muscular dystrophy in a female patient. Chin Med J 130(19):2273–2278 Yukihara M, Ito K, Tanoue O, Goto K, Matsushita T et al (2011) Effective drug delivery system for Duchenne muscular dystrophy using hybrid liposomes including gentamicin along with reduced toxicity. Biol Pharm Bull 34:712–716 Zambon AA, Muntoni F (2021) Congenital muscular dystrophies: what is new? Neuromuscul Disord 31(10):931–942 Zhong J, Chen G, Dang Y, Liao H, Zhang J, Lan D (2017) Novel compound heterozygous PLEC mutations lead to early-onset limb-girdle muscular dystrophy 2Q. Mol Med Rep 15(5):2760–2764 Zubrzycka-Gaarn EE, Bulman DE, Karpati G et al (1988) The Duchenne muscular dystrophy gene product is localized in the sarcolemma of human skeletal muscle. Nature 333(6172):466–469
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Axonal Degeneration, Impaired Axonal Transport, and Synaptic Dysfunction in Motor Neuron Disorder Sabra Parveen, Farheen Showkat, Neetu Badesra, Mohmmad Saleem Dar, Tariq Maqbool, and Mohd Jamal Dar
Abstract
Motor neuron diseases (MNDs) are progressive disorders of the neurological system that have a strong effect on upper and lower motor neuron systems. Genetic mutations that contribute to the occurrence of motor neuron diseases lead to loss of protein homeostasis, dysregulated RNA metabolism, dysfunctionality of mitochondria, and impaired vesicle transportation. All these factors contribute to the impairment of the shape of axons resulting in their retraction. Axonal transportation is widely associated with the trafficking of essential cargos, neurotransmitters from neurons to the body organs, and a responsive signal back from organs to the neurons. Dysregulation in this system leads to neurological consequences. Some common and fatal diseases that arise due to MNDs are amyotrophic lateral sclerosis (ALS), survival motor neuron (SMN), spinal muscular atrophy (SMA), and progressive muscle atrophy (PMA). These diseases reflect symptoms of muscle cramps, dysphagia, spasticity, muscle weakness, atrophy, disturbance of neuropsychiatric behavior, and loss of homeostasis. There is a strong correlation between MNDs and axonal transport impairment, as evidence suggests the defective anterograde and retrograde transport, malfunc-
S. Parveen · F. Showkat · N. Badesra · M. J. Dar (*) Laboratory of Cell and Molecular Biology, Department of Cancer Pharmacology, CSIRIndian Institute of Integrative Medicine, Jammu, India Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, India e-mail: [email protected] M. S. Dar Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh, India T. Maqbool Laboratory of Nanotherapeutics & Regenerative Medicine, Department of Nanotechnology, University of Kashmir, Srinagar, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_8
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tioning is considered an initial step in the development of neurodegenerative disease as well. Some commonly affected genes, such as DCTN1 and K1F5A, show a loss of functionality, thereby altering the axonal interactions. This chapter highlights the relationship between MNDs and impaired axonal transportation and their associated disorders. Keywords
Axon · Synaptic dysfunction · Motor neuron · Neuronal signals · Axonal transport
8.1 Historical Background The human body, a magnificent nexus of interactions, holds enormous potential to maintain its integrity. One such role is prominently played by the brain system, comprising of extraordinary neuronal connections. The neuronal system encompasses a specialized diversity of cells that are responsible for redirecting and receiving signals, essential for carrying human activity and homeostasis. The discovery of neurons traces back to the year 1740 when Emmanuel Swedenborg, a Swedish philosopher and scientist, anticipated about nerve cells and studied the brain anatomy. With the passing years, many new scientists of that time started recognizing these cells as essential parts of the nervous system. In the year 1833, Berlin-based scientist, Christian Ehrenberg, discovered nerve cells. Following year later in 1837, Evangelista Purkinje and Robert Remak individually reported about unmyelinated axons. From the year 1852 to 1865, numerous studies and investigations led to the recognition of axis cylinder, which was described as non-dividing nerve cell branch with long and uniform-caliber process. At the end of the nineteenth century, neuron theory surfaced and suggested that nerve tissue is genetic, anatomic, and a trophic unit, and exists independently as an individual cell, called as “neuron doctrine.” This theory suggested that the fundamental unit of nervous tissue is neuron—a cell capable of conducting the impulses. Referring to the theory it was also postulated that dendrites and cell body/soma act as recipients as they receive impulses from various neurons. Adding to it, axons were reported to be the units that transmit/pass arising impulses to the terminus. Noteworthy contributors to several studies conducted on nerve cell were Ramón y Cajal, Gustaf Retzius, Fridtjof Nansen, Sigmund Freud, Edward Schafer, Micháel von Lenhossék, Albrecht von Kölliker, and Carl Ludwig Schleich. In 1893, it was stated that the neural cell has a cell body, axons, dendrites, and a few other parts and they collectively make it a unit structure. With much deeper investigations, biochemical analysis, and invention of electron microscopy, neuron theory was modified with several different conceptions. Synaptic connectivity and neural connection had become the prime focus of the study. Moreover, the significance of biochemical signaling was defined. Stating this, it was found that there was a trans-synaptic transfer of impulses between different neurons, these signals are critical for neuronal survival. The studies and breakthroughs of the interesting neuronal cells have attracted the curiosity of researchers from broad groups. So, to explain and understand the mechanism, structure, and physiology of neurons,
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a wide array of studies have been conducted (Ludwig et al. 2022). Before proceeding further, it will be noteworthy to provide a brief aspect of neurons.
8.2 Introduction Neurons have a central role in the developmental process of the mammalian brain, formed by the initial transition of the neural stem and progenitor cells between symmetrical and asymmetric neurogenic divisions. Neurons are cells that are capable of carrying the message throughout the body but they are electrically charged cells (Orgel 1984). This means, they carry information via electrical and chemical components (Nguyen et al. 2023). Due to their remarkable capacity to receive and generate information, they feature as the most important cellular organization system of the human body (Carpenter et al. 1999). Newborn neurons travel radially in the embryonic dorsal telencephalon to the cerebral cortex with six-layer development (Pulvers et al. 2007). There are several kinds of progenitors with a wide range of biological features and cellular division mechanisms. To govern the amount, kind, and location of final neural cells, the conversion from proliferative to neuronal cell divisions necessitates a sophisticated regulatory system that allows neural specification, including cell-cycle exit, cellular differentiation, and migration of neurons, to proceed them all concurrently (Carpenter et al. 1999). As a result, the brain of an adult has a fraction of persisting stem cells that are astrocyte-like cells, residing in the dentate gyrus and sub-ventricle region of the lateral ventricle. This gives birth to the progenitors of neuronal cells that form neurons throughout. Neurons are classified into two categories: cells that are residing in the central nervous system (CNS) and cells that are residing in peripheral nervous system (PNS) (Bauerfeind et al. 1996). They have different physiological appearances and occurrences within these two systems, as in CNS, they can persist as nuclei when in clusters and as laminae and when found in layers. But in PNS, they normally occur as ganglia (Liem 1990). Neurons can have either excitatory, modulatory, or inhibitory effects. Along with these properties, they have motor, secretory, or sensory effects. Hence, the cytology of neurons is capable of promoting either top-down or bottom-up signaling transmissions. In this course, efferent neurons are responsible for transmitting top-down information starting from the brain to the periphery system. This type of signaling is concerned with locomotion. While afferent neurons are responsible for the bottom-up signaling, i.e., delivering alert signals to the brain. This is carried out in the opposite direction (Matsumoto et al. 1992).
8.3 Morphology of Neurons From the anatomical aspect of neurons, they are polymorphic and their classification is generally due to their size, shape, localization, and the types of signals they produce through synapsis. They have protruding structures or branch-like extensions known as dendrites, functioning as receivers of signals from other cells and
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organs. Axon is an essential structure of the neural body responsible for delivering and conducting impulses which propagate from a pre-synaptic neuron to the postsynaptic neuron. Axons have a specificity of either being myalated or unmyalated and these connections form an essential complex of neural system (Brady et al. 2005). As axons are the central focus of this chapter, thus will be discussed in detail below. The differential characteristics of neurons may pitch a question in the mind of readers, “ARE NEURONS DIFFERENT FROM OTHER CELLS OF THE BODY.” To answer this, neuronal cells are much like other cells of our body. Just like other cells, they too contain Golgi bodies, nucleus, mitochondria, etc. but they differ in a few or more characteristic features. Typically, a neural structure has a cell body, which is also known as soma or perikaryon. From one pole, extends dendrites and from opposite pole, axons protrude. Being the most polymorphic cell, researchers depicted the neuron as a spherical mass floating between nerve strands, but advanced studies revealed its specialized structures and a vast array of size and shapes. In humans, they vary in dimension from tiny, spherical cerebellar granule cells with a perikaryon of diameter between 6 and 8 mm to approximately 60–80 μm Purkinje cells that are pear-shaped and star-shaped anterior horn cells (Gaudet et al. 2011). Cell Body Unlike non-neuronal cells, the cell body has a cytoplasmic membrane that contains the nucleus and other organelles. Additionally, to perform typical housekeeping duties (such as cell maintenance), cytoplasmic organelles are in charge of neurotransmitter production (e.g. acetylcholine). Apart from this, they also allow cytoplasmic extensions to spread from its surface in the form of dendrites (Brady et al. 2005). Being the central part of the neuron and containing the nucleus, it also houses a conspicuous nucleolus. Within the nuclear region resides nucleochromatin, where dense heterochromatin-like structures reside. They are vesiculated and have dual distinguishable textures. Among them, one is made-up of bundles of filaments called, as Parsfibrosa and the other one is a thick granular structure, known as Parsgranulosa. Continuous with this is nucleoplasm that surrounds the nucleus and is occasionally extended with ER (endoplasmic reticulum). In between these two lies a 20–40 nm channel. The whole ER of a neuron actually generates most of the proteins for its usage due to the high requirement specification put on the cell. Together inner membrane and outer membrane join to create a diaphragm called as nuclear pore (García-Cabezas et al. 2018). The majority of neuronal cells contain Nissl substances, which are endocytic basophilic aggregates that spread widely throughout the cytoplasm. The dispersion of Nissl substances in a particular neuron is distinctive, so it can be exploited to identify neurons (Fu and Gordon 1997). Nissl compounds distribute along dendrites but do not enter the axon (Snider and Thanedar 1989). In most neurons, because of the irregular organization of ribosomes, it can be challenging to distinguish smooth endoplasmic reticulum from rough ER (Snider et al. 1992). A network of smooth, flat, and membrane-bound cristae is present in neurons, which were given a recognition by Palay and Chan-Palay, as hypolemmal cisternae. This forms the specialized part of the SER (smooth endoplasmic reticulum).
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These cisternae build a secondary membrane barrier in the cells between neuron’s plasmalemma. The gap among these cisternae as well as the plasma lemma is normally 10–12 nm. Another important organelle of neuronal cell is the mitochondrion. Mitochondria is known as oxidative phosphorylation center and its function is ubiquitous to neurons. It resides prominently in the synaptic endpoints and has a great role in maintaining neurotransmission activity (Snider et al. 1992). In neurons, the Golgi apparatus is made up of clusters of cisternae that are smoothwalled. It also has a multitude of vesicles (Markus et al. 2002). It is surrounded by a diverse array of organelles such as mitochondria, lysosomes, and multi-vesicular bodies. The Golgi body surrounds the nucleus of the cell where it extends into the dendrites for most neurons and is missing in the axonal portion. A 3D (threedimensional) examination of these structures indicates that stacks of cisternae occasionally perforate via openings that have circular geometries. The lysosomes in the neurons form the primary organelle in the management of cellular waste breakdown. It is abundantly present in neurons, where it may be detected at different developmental phases (Thayer et al. 2013). The core lysosome, which is a tiny, vesicular structure, is formed from Golgi saccules. Its role is to combine with phagosomes, which are membranes of waste-containing vacuoles, and discharge hydrolytic enzymes within them. The material that has been sequestered, subsequently is destroyed inside this vacuole, and thus the organelle transforms into a big electron-dense and secondary lysosome structure. Tertiary lysosomes are non- degradable material-containing residual structures, and some are represented in neurons via lipofuscin granules (Patton et al. 1997). Another important focus of the study is neurotubules. They are often scattered irregularly across the perikaryonal area of neuronal cells, and they are axially oriented in dendrites and axons. Therefore, they are made up of a compact arrangement, encircling the transparent lumen in the midst of which a structure of electron-dense region may be detected. In conjunction with the proteins dynein and kinesin, axonal neurotubules are known to be involved in axoplasmic transport including 5 nm, filamentous interconnecting side arms (Palay et al. 1968). In association with neurotubules, an intermediate filamentous structure is found, called as neurofilaments. They have a diameter ranging from 10 nm and exist in bundles with prominently in axons and rarely in dendrites. Within neuronal somata, neurofilaments tend not to have cross-bridges. A finer filamentous structure than neurofilaments is visible notably in the growth cones of developing axons. These actin-based structures typically 5 nm in size are classified as microfilaments (Westrum 1966).
8.3.1 Types of Neurons Neurons are diverse and this is reflected from their genetic make-up and anatomical features. Different types of neurons are listed be:
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1. Unipolar: This subtype of neuron has a single axon extending out from the spherical cell body, and the cell membrane lacks dendritic branching in other areas. These cells are most commonly seen in peripheral nerves and sensory ganglia (Jennes 2017). 2. Bipolar: In these neurons, from one end of the oval cell body, a single axon protrudes, while a single dendritic projection extends from another end. These cells can be found in the vestibular (hearing), olfactory, and ocular (retinal) systems (Butler 2002). 3. Multipolar: The number of progressions that originate from the soma can also be used to classify multipolar neurons. These cells contain multiple dendrites protruding from one end and a single axon that extends from the other end of the cell body. The cells seem fusiform or polygonal due to the many branching (Deiters and Guillery 2013). Multipolar cells include both motor neurons and interneurons and they are commonly present in the brain and spinal cord. 4. Pseudo-unipolar: In this cell type, soma is located in the dorsal root ganglia and it consists of a function that acts dually: i.e., it acts as an axon as well as dendrites. By this, it is understood that one branch is central (axonic), and thus travels to the spinal cord from the cell body, while the peripheral (dendritic) radiates to the cell body from the periphery (Marani and Lakke 2012).
8.4 Developmental Aspect and Regulatory Outlook in Neuronal Connections One representative nervous system has various components. That includes many types of neurons, glial cells, sensory cells, and muscles originating from their respective locations in the embryo. In the initial phase of neural development, they develop independently through a particular signaling program. Under the control of gene regulatory mechanisms and inductive signals, neurons are assigned their specific characteristics. Neuronal system develops from embryonic stem cells and, later in the period of differentiation, they transform into neural stem cells, which further differentiate into oligodendrocytes, astrocytes, and neurons (Ooi and Wood 2008). Given in Fig. 8.1 is a brief schematic diagram that represents how neuronal cells originate from neural stem cells into mature neurons. Neural patterning is an important part of neurogenesis. In this process, at an early stage, neuronal ectoderm divides along different axes, called as anterior– posterior axes and dorsal–ventral axes. This patterning has a great role in specifying neural precursors, e.g., spinal cord, hindbrain, forebrain, and midbrain. Various morphogens, viz., BMP (bone morphogenetic proteins), WNTs (wingless-related integration site), FGF (fibroblast growth factors), and Shh (sonic hedgehogs), coordinately work to determine neural progenitors (Liu and Niswander 2005). Numerous researchers have discovered critical transcription factors that tightly regulate this system and manage the pluripotency of embryonic stem cells. They also identified their role in the process of self-renewal. One core regulatory system consists of NANOG (Nanog homeobox), Sox2
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Dendrites. Axon Hillock
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A. Neural stem cells. B. Neural progenitor cells. C. Neuro blast. D. An adult neuron. It consists of cell body, and other organelles including Golgi bodies, mitochondria, microtubules, ribosomes, Nissl substance, neuro-filament, microfilament, a prominent nucleus and nucleolus
Myelinated axon
Axon terminals.
Fig. 8.1 Displays a visual representation of how the formation of an adult neuron from neural stem cells leads to the development of a well-defined neural cell that consists of the cell body containing various necessary organelles and its extending axon body
(sex-determining region Y-Box-2), and Oct4 (octamer-binding transcription factor-4). These factors are crucial for maintaining the expression level of many genes, as well as regulating their own expression. Hence, any disruption in this network can lead to drastic consequences. This circuit is self-sustaining, once activated, maintains the differentiation of ES cells into particular cell fates. This needs external signaling through secreted chemicals via BMPs (Chang et al. 2020). The expression of NANOG is of utmost importance for maintaining stable ES cells. The fluctuating expression of NANOG over time in ES cells shows its different effects. The high levels of NANOG hinder the differentiation of ES cell as compared to its low expression, which provides a great opportunity for ES cell differentiation (Jung et al. 2022). The expression of Sox2 is also crucial for preserving Oct4 levels. Oct4 works in tandem with additional (Sox) proteins produced in Embryonic Stem cells, such as Sox 4, 11, and 15 to trigger the production of selective target genes, including Oct4 itself, but in the absence of Sox2 (Stevanovic et al. 2021). Nevertheless, the deletion of Sox2 causes increased expression of the gene Nr2f2, which codes for a steroid hormone receptor that represses Oct4 production, and decreased expression of the gene Nr5a2, which encodes a receptor for steroid hormone that stimulates expression of Oct4 (Chang et al. 2020). Hence, the loss of Sox2 results in decreased Oct4 levels as well as ES cell differentiation despite the fact that Sox4, 11, and 15 may directly augment Oct4 expression in place of Sox2 (Lein et al. 2007). The point that ectopic production of transcription factor Oct4 is enough for blocking differentiation of ES cells,
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which emphasizes the importance of the influence on Oct4 levels in ES cells lacking Sox2 (Masui et al. 2007). Embryonic Stem cells commit to neural cell lineages and develop into neural or glial cells in response to a variety of incoming signals such as fibroblast growth factors, retinoic acid, suppressive BMP signals, and WNT/NOTCH signaling. A balance of contrasting transcription factors results in cell destiny determination for the maintenance, or differentiation towards glial or post-mitotic neurons. In the development of neurons from neural progenitors and the determination of neuronal cell subtypes, homeodomain and basic helixloop-helix (bHLH) transcription factors, including Math1, Mash1, and neurogenin, collaborate in action and are involved in carrying out this process in the nervous system. Most neurons develop towards two fates, which can be either glutamatergic, which is an excitatory neuron, or GABAergic, which exhibits an inhibitory neuron phenotype. GABAergic neurons in the cerebellum are defined by pancreas-specific transcription factor 1a (Ptfla), a bHLH transcription factor that arranges as a heterodimer with Rab- and DnaJ-domain containing (RBJ) protein. The sub-ependymal zone’s neural stem cells can produce GABAergic neurons when the bHLH gene, Mash1 is expressed (Dennis et al. 2019). Only glutamatergic neurons develop in the absence of Ptf1a in the cerebellum. However, Ptf1a’s ectopic expression in glutamatergic precursors is enough for changing neurons to the GABAergic phenotype (Cinar et al. 2005). Tlx1 and Tlx3 are homeobox-containing transcription factors that support glutamatergic neuron specification and prevent GABAergic differentiation in the spinal cord. Lbx1 (ladybird homeobox 1) is a regulatory gene, which is responsible for the determination of neural fate. Due to its presence in glutamatergic neurons, the differentiation of GABAergic is prevented by Tlx1 and Tlx3 expressions. According to an experimental investigation, mice without Tlx3 exhibit enhanced GABAergic differentiation, which is caused by the presence of Lbx1 (Borghini et al. 2006). Yet, curiously, in mice lacking both Tlx3 and Lbx1, normal glutamatergic differentiation is restored. In certain cells, interactions between various transcription factors allow them to promote various cell fates. The expression of Neurogenin2 in the forebrain encourages the development of glutamatergic neurons and, in the spinal cord, in conjunction with oligodendrocyte transcription factor 2 (Olig2), encourages the differentiation of motor neurons (Hulme et al. 2022). The thorough identification of all target genes for a given transcription factor during development has not been done, despite the knowledge of such mutually antagonistic connections between individual transcription factors. Even while obtaining such information would be technically tough, it would be the first step in comprehending the transcription-factor networks that define the sorts of neuronal cell types. Many cell types created at different times depend on the activation of transcription factors; neuronal subtypes are frequently formed sequentially from the same pool of multipotent progenitors (Santiago and Bashaw 2014). Listed in Table 8.1 are a wide range of associated biomarkers that are critical for the process of neurogenesis.
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Table 8.1 Role of various biomarkers in neurogenesis Biomarker Role and function Emx2 Empty spiracles homolog 2—a transcription factor participates in the development of the cerebral cortex including proliferating neuroblasts Sox5 Sex-determining region Y-box 5 is a transcription factor belonging to the Sox family, critical for deep-layer neuron migration during initial stages of neuronal development Bcl11b Also called Ctip2, B-cell leukemia/lymphoma 11B, a zinc finger transcription factor that participates in the development of subcortical axon Tbr1 Tbr1, T-box brain factor 1, a transcription factor, found to be functional by associating with Sox5 and regulating early-born neurons in multiple shapes throughout the embryonic development Fezf2 Also known as FEZL, ZFP312 is one of the important members of FEZ family zinc finger and functions as a transcription factor. Fezf2 can be found in L5 cortical spinal (CS) neurons at a very high level and plays a fundamental role in the CS tract development Satb2 This AT-rich sequence-binding protein is a matrix-attachment region interacting transcription factor, which can primarily concert the nuclear matrix-attachment regions and is involved in remodeling chromatin. SATB2 is considered as an active transcriptional modulator and regulates a variety of region- specific markers for cortical projection neurons Cux1/ Cux1/Cux2, cut-like homeobox 1/2, markers specific to the Cux2 upper layer, participating in the fundamental regulation of the late neuronal differentiation, dendritic branching, and synaptogenesis in specific upper-layer (L2–3) cortical neurons Pou3f2 and Pou3f3
Sox1
Nr2f1
NeuroD
PAX6
(POU class 3 homeobox 2, also named asBrn-2) and (POU class 3 homeobox 3, Brn-1) both belong to class III POU family transcription factors that have an important part in neural differentiation. POU3F2/POU3F3 is believed to be involved in upper-layer neuronal migration and identification Sox1 is expressed exclusively in the CNS and possibly functions as the initial marker for neural fate choices of embryonic stem cells Nr2f1 (also known as Coup-tf1) belongs to nuclear receptor subfamily 2. It plays an important role in neocortical regionalization Type of neurogenic differentiation transcription factor, one of the members of family basic helix loop-helix protein, playing a part in neuronal progression, also classified as a differentiation indicator for neurogenesis Paired box 6, belonging to the paired box (Pax) family. Pax6 seen in the cells emanating from the embryonic neural development and adult neurogenic niches. It also regulates NSCs proliferation and differentiation
References Cecchi et al. (1999) Kwan et al. (2008) Arlotta et al. (2005) Hevner et al. (2001), Han et al. (2011) McKenna et al. (2011)
Britanova et al. (2008)
Cubelos et al. (2010), Benavides- Piccione et al. (2006) Sumiyama et al. (1996), McEvilly et al. (2002)
Aubert et al. (2003) Alfano et al. (2011) Kawai et al. (2004)
Osumi et al. (2008)
(continued)
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Table 8.1 (continued) Biomarker Role and function Sox2 Sox2 also named as SRY (sex-determining region Y) box 2, one of the members of Sox family of transcription factors, playing vital roles in distinct stages of mammalian development. It is highly expressed in embryonic stem cells and adult NSCs during development and is important for NSCs proliferation and differentiation Nestin Nestin, neuroepithelial stem cell protein, which displays transient expression in adult NSCs, immature neural progenitor cells, and disappears on the cell differentiation. It has been commonly exploited as a marker of NSCs in the embryo as well as in adult brain Tbr2 T-box brain gene 2 belongs to mammalian brain-specific T-box gene family, expressed in some specific regions developing brain. And has been found to play a part in adult neurogenesis
References Ferri et al. (2004)
Lendahl et al. (1990)
Kimura et al. (1999)
8.5 Neuronal Signals and Synaptic Network Regulators Synaptic transmission is the mechanism through which neurons talk to other cells. Although the number of synaptic connections in the brain may be inconceivable to us, they provide a perfect framework for investigating the molecular processes that underlie chemical signaling. A variety of tiny organelles packed with biologically active small chemicals populate the presynaptic nerve terminal. To make a connection with post-synaptic destinations that are far from the neuronal cell body, neurons grow lengthy axons. The release of chemical messenger molecules, known as neurotransmitters in a controlled manner, is the primary mechanism by which neurons in the peripheral and central nervous systems communicate with one another (Volknandt 1995). Calcium influx causes the presynaptic terminal to release neurotransmitters. By attaching to the proper receptors, the released transmitter molecules trigger a physiological reaction. The synaptic vesicles are highly specialized organelles responsible for maintaining neurotransmitter uptake, storage, and stimulus-dependent release. They are important for synapses, and various different proteins serve as the functional carriers for their diverse roles in synaptic transmission (Aalto et al. 1993). As shown in Fig. 8.2, various cellular organelles and proteins function in tight regulation for neurotransmission. Recently, varied components of tiny synaptic vesicles were categorized in detail at the molecular level. Proteins that are membrane-associated or membrane-integral have been found in synaptic vesicles. Proteins like the proton-pumping (V-ATPase), vacuolar proton ATPase, the SV2 protein (synaptic vesicle protein), or the neurotransmitter transporters are in charge of transporting tiny compounds (Bajjalieh et al. 1992). Additionally, essential proteins perform different functions such as exocytosis (synaptotagmin), docking of synaptic vesicles to the plasma membrane (VAMP), and putative pore creation (synaptophysin). Moreover, synaptic vesicle- associated proteins control other functions such as assisting binding of proteins, e.g., GTP-binding proteins, synapsins, and trafficking of synaptic vesicle in the
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Fig. 8.2 Communication between pre- and post-synaptic neurons via different chemical effluxes and their passage as neurotransmitters. In pre-synaptic neurons, signals are packed in vesicular forms
nerve terminal, guiding of plasma membrane at active regions, and functional modulation of vesicle proteins by phosphorylation in the nerve cells. Another important protein, CaM kinase II (calcium-calmodulin-dependent protein kinase II), also has a significant role in maintaining the plasticity of neurons for synapsis (Buckley and Kelly 1985). This serine/threonine kinase is responsible for regulating various states of enzyme activation and Ca2+ conversion. The synaptic vesicle transporters, synaptotagmin, synaptophysin, and synaptobrevin, all fall under this group of membrane-bound proteins. The biggest subunit of the proton-pumping V-ATPase is an integral protein found in the membrane, and the multi-meric structure of the enzyme has a mostly cytosolic alignment (De Camilli et al. 1993; Zimmermann and Vogt 1989). Molecular characterization of various proteins determines their importance in synaptic transmission and in this section, we will briefly enlist their roles. 1. SV2 (synaptic vesicle protein 2): Buckley and Kelly discovered it and designated it as an abundant and ubiquitous vesicle protein present in tissues of endocrine and neural systems. The six C-terminal transmembrane domains in SV2 have a decent homology to the plasma membrane transporter for neurotransmitters, whereas the six most domains of N-terminal are strongly similar to a differ-
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ent subfamily of transporters that comprise the human glucose transporter (Scranton et al. 1993). Research has shown that an electrochemical gradient is also necessary to drive neurotransmitter transmission into synaptic vesicles. Thus, in chromaffin granules, the idea that uptakes of transmitters are controlled in an electrochemical manner was demonstrated (Iwase and Martin 2018). The proton transporter known as V-ATPase creates this gradient and is present on the membranes of synaptic vesicles (Stjärne 1989). 2. V-ATPase is a massive hetero-oligomeric protein unit that has nine distinct components with varied stoichiometries, and it has a mass of around Mr 750,000. The catalytic domain, which is composed of different subunits, such as one Ac39 (39,000), three (3) A (Mr 70,000 each), three (3) B (58,000), one (1) C (40,000), one (1) D (34,000), and one (1) E units, is exposed to the cytosol. One A (20,000) and four C (16,000) subunits combine to form the membrane-spanning proton channel. The vesicle lumen houses the majority of subunits of transmembrane Acll6 (116,000) as well as the associated sugars. On the membrane surface of synaptic vesicles, knob-like protrusions are produced by the three-dimensional V-ATPase architecture (Volknandt et al. 1991). There is a dependency of H+electro-chemical gradients in the transmembrane region and it is maintained by an electrogenic system on neurotransmitter transport into synaptic vesicles. All cells have V-ATPases, which stimulate and energize a huge variety of active transportable organelles (Gogarten et al. 1989; Matthew et al. 1981). 3. Synaptotagmin: In the synaptic vesicle lumen, the amino terminus of synaptotagmin is glycosylated. It possesses a membrane-spanning domain, and the cytoplasmic regions of the two PKC (protein kinase C) homologous repeats (Courtney et al. 2019). PKCs with calcium-dependent modulation have the C2 regulatory domains resembling synaptotagmin. Strong calcium/phospholipid binding only requires a C2 domain from synaptotagmin. This process of calcium sensing on the surface of synaptic vesicle approximately binds up to the four molecules of calcium per protein of synaptotagmin at the half-point of coordinated calcium binding and at a 5–10 pM concentration (Perin et al. 1991; Volknandt 1995). Because of these characteristics of synaptotagmin, the calcium mediated triggering in synaptic transmission is a great contender. Analyses conducted on in vitro studies show that synaptotagmin communicates with the neurexins in a calcium-independent approach. Synaptic vesicle exocytosis is mediated by synaptotagmin and neurexin. Hence, regulating synaptotagmin controls neurotransmitter release. Another important protein, CaM kinase II (Casein kinase and calcium-calmodulin-dependent protein kinase), is studied to phosphorylate synaptotagmin (Brose et al. 1992). The coordinated interaction of calcium and phospholipids by synaptotagmin is thought to require multimerization of the protein. A number of methods, such as alternative splicing, phosphorylation, or proteolytic alterations, regulate synaptotagmin multimerization. Also, calcium causes modifications in their conformations (Popov and Poo 1993; Elferink et al. 1993). 4. Synaptophysin: Two members that have been most strongly linked to one another are synaptophysin and synaptoporin, both of which are known as synaptophysin II. These proteins are particularly found in synaptic vesicles (Popov
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and Poo 1993). The transmembrane domains including two little cytoplasmic segments close to the membrane are conserved areas of synaptophysin family members. Despite their remarkable similarity, these two proteins can also be found on the same organelle, indicating the isoform’s functional diversity. Tyrosine-rich vesicle, pp60, and CaM kinase II are present in synaptophysin (Régnier-Vigouroux et al. 1991). Synaptophysin may also form homo-oligomers with four to six monomers. When hexameric synaptophysin is amalgamated into synthetic membranes, it can create enormous conductance channels (Rubenstein et al. 1993). Synaptophysin and synaptoporin also possess structural similarities to connexins, which are proteins that create gap junctions. Thus, this facilitates the the opening and fusion of a gap junction, allowing neurotransmitters to be released (Evans and Cousin 2005; Thomas et al. 1988). 5. Synapsins “The reserve supply of synaptic vesicles”: A category of peripherally related proteins known as synapsins is essential in anchoring of synaptic vesicles at nerve terminals and during the beginning of synaptic vesicle exocytosis. In the mammalian brain, there are two polypeptides referred to as synapsin I and phosphoprotein 1, both have approximate molecular weights of 86,000 and 80,000, respectively (Ueda and Greengard 1977; Whittaker et al. 1972). The alternative splicing of two genes produces Synapsins. This results in the production of four distinct polypeptides, known as Ia and Ib and IIa and IIb synapsins, which have variable levels of expression throughout the nervous system. Synapsin-alternative I’s mRNA processing results in phosphoproteins that are very similar to one another and vary only within their brief C-terminal regions. In a study, synapsin I was shown to be exclusively confined to micro-vesicles in rat neurohypophysis at the terminals of neurosecretory cells. Synapsin I is not present in chromaffin cells in the adrenal medulla; however, it is prevalent in the nerve terminals of synaptic vesicles so that it communicates synapses with many of these cells (Llinás et al. 1991). Synapsins are linked to the cytoskeletal components of synaptic vesicles and interact with them (Nichols et al. 1992). Synapsins also communicate with filaments of actin, brain spectrin, and microtubules. In addition to this, PKC, (PKA) cAMP-dependent protein kinase A, and CaM kinase II, there are other protein kinases that phosphorylate the synapsins and regulate its bioactivity (Liu and Murray 2012; Kennedy et al. 1983). The cytoskeletal binding activities and vesicles of synapsin I are predominantly regulated by Ca2+-mediated CaM kinase II phosphorylation. Phosphorylation of synapsin I takes place at two carboxy-terminal locations when Ca2+ levels are high, which lowers the affinity of the protein binding to actin filaments and vesicles (Ashpole et al. 2012). The unit of a vesicle-associated CaM kinase II at a location separated out from the catalytic domain carries the synapsin vesicle-anchoring site. Synaptic vesicles and actins are coupled to dephospho-synapsin, whereas phospho-synapsin has the potential to liberate synaptic vesicles from the actin networks. The phosphorylation of synapsin modifies signal transduction by controlling the number of vesicles that are capable of exocytosis. Dephospho-synapsin has also been hypothesized to
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control the cytoskeletal actin, by enhancing the number of actin filaments (Nichols et al. 1992). Recently, there have been discoveries of synapsin modifications close to the location of CaM kinase II phosphorylation. A proline-directed protein kinase phosphorylates this area, which is then altered by O-linked glycosylation. Inferring that synapsin activity may play a part in the control of synaptic transmission, all of these alterations offer potential targets of synaptic regulation (Perin et al. 1990). Thus, synaptic vesicles are crucial to synaptic transmission. They are recognized as important components participating in synaptic processes such neurotransmitter reception, retention, and stimulus-dependent release (Volknandt 1995).
8.6 Mechanical Properties of Axon and Axonal Transport Axons, which are roughly 1 μm in diameter, serve both supporting structures and means of intra and inter-neuron interaction (Lee et al. 2019). A neuron is composed of many axons and the axonal membrane is made up of a phospholipid bilayer with proteins embedded in it. Most of the proteins are responsible for voltage-gated ion channels which are essential for the propagation of electrical signals between neurons because they allow ions to pass into and out of the membrane (Nelson and Jenkins 2017). Most neurons are myelinated, which means they have the segmented coverings known as the myelin sheath that wraps around the axon while others are unmyelinated (Deiters and Guillery 2013). Axons can be equated to have a regular, uniaxial arrangement that includes all essential components of the cell cytoskeleton. The axonal cytoskeleton is generally composed of a core containing neurofilaments, aligned and packed microtubules, and an actin cortex connected towards the plasma membrane. Similar to certain other cells, molecular motors enable the axon to produce active contractile tensions (McCormick and Gupton 2020). Axons are anticipated to play significant roles such as axonal retraction following damage, during rewiring, as well as stretching while limb movement. Axons that are thicker and more densely myelinated are faster and have more effective reflex-based circuits (Spillane et al. 2011). In contrast, the autonomic nervous system’s pain and hunger sensors contain thin, weakly myelinated neurons and generate slower signals (McCormick and Gupton 2020). The cytoskeleton’s structure is a crucial component of axonal architecture and is interesting since it differs from the dendrites in terms of composition as well as organization (Muzio and Cascella 2020). Given the importance of axons and its related circuits, dysregulations in these circuits are connected to the etiology of neurodevelopmental illnesses including intellectual impairment, autism, and other wide spectrum of disorders (Samson Jr. 1971). These circuits gradually start to break down in neurodegenerative disorders. The so-called growth cone, initially identified in 1890 by the Spanish histologist Santiago Ramón y Cajal (1852–1934), reported them important (Öztürk and Koç 2022). In addition, an environment that surrounds the axon influences how the nerve terminal grows and reaches its ultimate goal. Environmentally attracting or repellent chemicals react with receptors on the growth cone and subsequently cause changes to the cytoskeleton. Particularly, the cytoskeleton creates tiny extensions, or filo-podia, that
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resemble micro spikes and include bundles of actin filaments (F-actin). These additional cytoplasmic extensions are separated by flat, dense actin areas, called Lamello-podia, that resemble a veil (Ozcan 2017). In summation, microtubules polymerize into the growth cone and direct the extension activity via filopodia and lamellopodia after interacting with environmental stimuli (such as netrin, ephrins, and semaphorins). These stimulating factors may be external to the axon or present at a distance and influence axonal activity (Muzio and Cascella 2020). Another worth-mentioning structure in axons is the axon hillock, which is a cone-shaped portion of the axonal architecture. This is where the axon joins the soma. Because action potentials start within that region of the axon, it has a significant functional significance. In other terms, the processing of incoming data from other neurons occurs in this area of the neurolemma (McCormick and Gupton 2020). It serves as a triggering region where the action potential is generated whether or not it follows the aggregation of incoming graded excitatory (EPSPs, or excitatory postsynaptic potentials) and inhibitory (IPSPs, or inhibitory postsynaptic potentials) potentials. The potential is conveyed through the axon in a persistent or saltatory fashion (Berry et al. 2018). Axon hillock contains fragments of Nissl material, 30–40 μm perikaryon, and various myelinated components (Takenaka et al. 1998). The numerous axoplasmic components in this segment of the axon start to structurally coordinate in longitudinal patterns. There are also present mitochondrion and neurofilaments. Moreover, there are microtubules, which are organized into fascicles and are then joined by sidearms. Axonic synapses may develop in this area functionally. It is noteworthy that a thick granular layer resembling nodes of Ranvier is possibly seen in the axolemma of the axonal area where action potentials arise and begin their processivity (Samson Jr. 1971). Recent investigations revealed that action potentials might start not only at the axon hillock but additionally within this first axonal segment (Muzio and Cascella 2020).
8.7 Axonal Transport Axonal transportation, a bidirectional ATP-dependent mechanism, is how neurons move a variety of chemicals via axon microtubules. RNAs, proteins, and organelles are transported anterogradely to the tip of the axon from the cell body to reach growth cones and transmit to synapses (Sleigh et al. 2019). This process is power driven by the kinesin motor protein superfamily. On the other hand, retrograde movement in the reverse direction is facilitated by cytoplasmic dynein. Dynein is crucial for functions including signaling of neurotrophic factor, autophagy- lysosomal-mediated degradation, and reaction to the nerve damage (Chico et al. 2009). To ensure effective transport in the neurons, complex protein kinase signaling pathways and post-translational microtubule changes regulate the axonal transport system, which includes important motor adaptor proteins in addition to microtubules (Zhao et al. 2016). Due to the relentless energy requirements and total distance across which cargoes are mobilized, it should not be a surprise that genetic instability of strongly linked cellular processes like endo-lysosomal sorting,
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autophagy, and mitochondrial dynamics, as well as genetic changes in the axonal transport machinery can cause neurological diseases. Abnormalities in axonal trafficking are notably linked to Charcot-Marie-Tooth disease (CMT), ALS, and Parkinson’s disease, along with hereditary and acquired peripheral neuropathies (Zhao et al. 2016). Additionally, age imposes a greater factor in this aspect. As people age, transportation capacity deteriorates, making it a key risk factor for many degenerative diseases of neurons. Nevertheless, not all payloads appear to impact in the same way. Thus, the connection between poor transport of axons and neuronal disease is often complicated (Puls et al. 2003).
8.7.1 Association of Genes in Axonal Transport Forty-five genes of mammals encode the members of the superfamily of the kinesin proteins, that is divided into 15 subfamilies and include 38 genes that are expressed in the nervous system (kinesin 1 to kinesin 14b). The three kinesins, 1, 2, and 3, appear to be crucial for axonal transport. Kinesin heavy chains dimer, encoded by KIF5A, KIF5B, and KIF5C, as well as a dimer of kinesin light chains, encoded by KLC1, KLC2, KLC3, and KLC4, make up kinesin 1 motors (Yamada et al. 2003). Another important protein family dynein is also necessary for retrograde transport of axons (Cheng et al. 2014). The existence of a massive (approximately 1.4 MDa) multi-subunit motor complex called cytoplasmic dynein is encoded by DYNC1H1. This family is composed of two heavy chains of dynein, two intermediate chains coded by DYNC1IC1 and DYNC1IC2, two light intermediate chains, encoded by DYNC1LI1 and DYNC1LI2. In the family of light chains, different associations are studied in dynein. • T-complex-associated family type: these complexes are encoded by DYNLT1, DYNLT2, DYNLT2B, DYNLT3, DYNLT4, and DYNLT. • LC8-type family: these are encoded by DYNLL1, DYNLL2, and DNAL4. • Road-block family type: these are encoded by DYNLRB1 and DYNLRB2. (Scoto et al. 2015; Puls et al. 2003). The extra dynein subunits are assembled onto a dynein heavy chain dimer to create the core motor, and the resultant complex attaches to microtubules and hydrolyzes ATP. It is interesting to note that this motor unit lacks significant processivity on its own, is dependent on other adaptors and accessory proteins for effective cargo transport, and performs its wide range of tasks (Huynh and Vale 2017). Both kinesin and dynein functions are dependent on adaptor proteins, which bind various payloads. A key cofactor for dynein is dynactin, which is a complex of 1.1 MDa, made up of 23 subunits arranged around with a brief, actin-like filament consisting of “actin-related protein 1” (Berry et al. 2018). Dynactin aligns the motors and attaches dynein to trigger possessive motion. Various activating adaptors consist of the Hook proteins3 (HOOK3) and Bicaudal D homolog 2 (BICD2) (Zhao et al. 2016). The family of BICD proteins (BICD1, BICD2, BICDR1, and
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BICDR2) is a powerful amplifier of (−) minus-end-directed transport that significantly boosts the processivity of such dynein–dynactin complex. Coiled-coil domains also present in the BICD family, similar to certain other activating adaptors, and are essential for the association of dynein–dynactin complex proteins (Zhao et al. 2016). LIS1 and NDEL1 are two additional crucial regulators of dynein (Shu et al. 2004). Directly attaching towards the motor domain of dynein, LIS1 can either enhance or reduce microtubule binding, depending on how it interacts with the dynein complex. Moreover, research suggests that this protein has the ability to alter dynein motion. Coiled-coil-containing protein NDEL1 interacts with LIS13 and dynein via the latter is intermediate chain and LC8 subunits. It has been demonstrated that NDEL1 connects LIS1 to the dynein complex, although it is unclear whether NDEL1 improves or inhibits LIS1 function (Pandey et al. 2022). Since kinesin motors are more diverse than the single dynein complex, kinesins appear to depend on relatively few other adaptor proteins. Thus, on the other hand, kinesin is a strong mechanochemical protein that works to polarize the movement towards the plus ends. The majority of kinesin adaptors, such as HAP1, JIP1, and TRAK1, also function as dynein adaptors. At least in some cases, the common bidirectional adaptors include overlapping kinesin and dynein interaction domains, which raises the possibility of a binary switch controlling the mode of transportation (Sleigh et al. 2019).
8.7.2 Transportation of Cargos and Cellular Moieties Across Axons Based on pulse-chase tests and utilizing radiolabeled amino acids, axonal transport has been categorized into rapid and slow groups. Rapid axonal transport carries a variety of payloads, such as vesicles and membrane-bound organelles, between 50 and 200 mm per day, while slow axonal transport, which travels at a speed of between 0.2 and 10.0 mm per day, is essential for the mobilization of materials including cytoskeletal proteins (such as tubulin and actin) (Guedes-Dias and Holzbaur 2019). Quick axonal transport may deliver cargo between the cell body and the tip of axons, that is, for a 1 m-long motor neuron in less than a week, but slow axonal transportation can take a longer time. Slow axonal transport is also thought to transfer more than three times as many proteins as fast axonal transport (Roy 2014). As slow axonal transport happens over a lengthy period, imaging it is technically difficult. As a result, most of what we know about the dynamic characteristics of cargo trafficking through axons came from live-imaging investigations of rapid axonal transport, which started in the early 1980s (Surana et al. 2020). Transportation may be broken down into different phases, such as localized delivery, active transport, and movement of proteins. The cargos and other organelle- transport via axons are also controlled in a variety of ways, which include binding, integration of opposing motors bound to the same cargo by associated scaffolding proteins, activation and localization of motors by adaptors or other binding partners, and modification of the microtubule track through PTMs or MAPs
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(microtubule-associated proteins) binding (Waites et al. 2021). Such processes result in “compartment-specific modulation and regulation,” where the control of transportation may be separately tuned in the proximal axon or distal tip, and “cargo-specific changes in transport,” where mitochondria, autophagosomes, endosomes, lysosomes, and other granules are trafficked (Atherton et al. 2014; Monroy et al. 2018; Maday et al. 2012). The role of microtubules is noteworthy when referring to axonal transportation and the consistent production of correctly orientated microtubules is necessary for axonal extensions. When a neuron develops, the centrosome eventually disappears, but the tubulin ring complex (TuRC), which also maintains neurite extension, maintains a centrosomal microtubule nucleation. Emerging research has revealed that Augmin, which is a protein complex essential for the microtubule formation in a centrosome-independent pattern, plays a key role in controlling the polarity of axon microtubule nucleation (Sánchez-Huertas et al. 2016). Along with NEDD1, Augmin presumably governs the shape of microtubule network construction by recruiting TuRC to microtubule lattices to initiate microtubule branching. It was further discovered that SSNA1, which is a microtubule stabilizer, causes branching microtubule polymerization (Sánchez-Huertas et al. 2016; Kuijpers and Hoogenraad 2011). The presence of SSNA1 at the locations where axonal branches raise the possibility that it contributes to the specification of microtubule plus-end polarity for developing axonal extensions (Basnet et al. 2018). Moreover, the interaction of actin cytoskeleton with Septin-7, present at the base of filopodia and drebrin, and in the proximal area of filopodia, helps microtubule plus-end directing into axonal branches. Thus, necessitating its function in neural circuits (Hu et al. 2012). Axonal pathfinding, target innervation, adaptability, and survival all depend on long-distance interaction between the nerve terminal and the cell body. The well- known Neurotrophin family, which includes the growth factors (NT-3 and NT-4) neurotrophin 3 and 4, (BDNF) brain-derived neurotrophic factor, and (NGF) nerve growth factor are frequently generated within post-synaptic cells which start signaling at axon terminals by attaching particular Trk receptors (tropomyosin/tyrosine kinase receptor) (Reichardt 2006). According to numerous areas of research, these long-range impulses are transmitted through transport by “microtubule-dependent dynein motors.” While there are other theories, it is generally agreed that many, if not most, parts of retrograde signaling pathways involve the passage of a “signaling endosome” through vesicles (Lindsay 1988). According to the “signaling endosome paradigm,” Trk receptors internalized by clathrin- mediated or pincherdependent endocytosis after a ligand binds to them and activates them are within the distal axon. To initiate a surviving response, the resulting vesicles carrying the ligand–receptor complexes are transferred to the cell body in a retrograde fashion. This cascade and the association of RAS-MAP kinase, PLC, and PI3-kinase pathway activation have also been seen in vesicles containing neurotrophins and Trks (Reichardt 2006; Aksamitiene et al. 2012). Hence, these vesicles include coordinating complexes that may completely replicate the signaling events that take place at the nerve terminals. These pathways are hypothesized to be induced either in conjunction with signaling endosomes or in the cell body following the passage
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of the signaling endosome (Hanz et al. 2003; Pugazhenthi et al. 2011). Additionally, crucial kinases such as Rsks and Erk5, which are found in the cell body, travel to the nucleus wherein they phosphorylate and then stimulate transcription factors like CREB, to drive neurotrophin-induced gene expression. A current study, however, suggests that CREB is actually a part of the signaling endosome. It is reported that the local translation of the mRNA encoding CREB occurs in the axon in relation to NGF-stimulated distal axon stimulation. The researchers propose that axonally produced CREB is carried across the axon with the TrkA-signaling complexes since it co-localizes with both P-Trk and P-Erkin the axons (Liu and Ma 2011). An additional method of dynein-associated transportation specificity is through post- translational cargo modification. The “RNA-binding protein La” is transported retrogradely because of sumoylation in axons. La that has been sumoylated only binds to dynein, enabling retrograde transport (Lenzken et al. 2014). Kinesin motors carry La anterogradely into axons, where it is covalently changed by the introduction of tiny ubiquitin-like modifying polypeptides. It is intriguing to think about how similar post-translational alterations, such as sumoylation for retrograde transit, can also target components of signaling endosomes (Henley et al. 2014). Another transcription factor serum response factor (SRF) is also important for NGF- dependent axonal development and terminal branching through the activation of MEK/ERK and MAL signaling pathways. Additionally, NGF stimulation of axon terminals controls SRF-dependent gene expression. The long-range axon guiding method that neurons can employ as consecutive neurotrophin stimuli is also suggested by the signaling endosome concept (Gorosito and Cambiasso 2008).
8.7.3 Axonal Impairment and Development of Disease Motor neuron diseases influence several motor systems including skeletal muscles, neuromuscular junctions, lower motor neurons, and corticospinal higher motor neurons. Numerous phenotypes of motor neuron diseases, viz., muscular atrophy, weakness, and spasticity, result due to impairments of these systems. One of the initial molecular processes leading to neurodegeneration is axonal transport abnormalities. According to existing examinations, axonal transport abnormalities are related to the pathogenesis of MNDs (Guedes-Dias and Holzbaur 2019). The longevity of motor neurons depends on optimizing axonal transport since their axons are often relatively long. As a contributing factor to the dysfunction of neurons in a number of neurodegenerative motor neuron illnesses, axonal transport restriction is receiving more attention. In the motor neurons of highly specialized cells, the longest axons (more than 1 m long in humans) are typically interconnected to the soma with synaptic locations away from the cell body (Ikenaka et al. 2012). Even though axons that make up more than 99% of a cell’s volume, the cell body plays a crucial role in protein and lipid synthesis, which are essentially involved in axonal transport and a healthy neuronal functionality. Thus, a dynamic transportation is necessary to move functional organelles, damaged organelles, and neurotrophic elements from the
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axon terminal to the cell body as well as to deliver freshly produced materials to the axon. The cytoskeletal frameworks of microtubules as well as actin filaments, together with a set of specialized motor proteins, are the main contributors to axonal transport. A growing number of studies connect motor neuron degenerations notably SBMA (spine and bulbar muscular atrophy), hereditary spastic paraplegias, and SMA (spinal muscular atrophy), with problems in axonal transport (Holzbaur 2004). Further investigations discovered abnormalities in the genes that encode the kinesin 1 motors (KIF5A) in some types of HSPs; multiple missense genetic abnormalities in the dynein gene in the “Loa and Cra”, and mutations in the dynactin-1 gene, are linked to a familial form of lower motor neuron disease (Puls et al. 2003; Fichera et al. 2004; Hafezparast et al. 2003). These mutations are believed to affect certain inherited forms of motor neuron diseases and are also brought on by membrane-associated protein dysregulation that impedes the effective transport of cargos like mitochondria and endosomes (Chao 2003). “Severe lissencephaly” is due to mutations in the dynein-binding protein Lis1. There is a contrasting role played by this protein as its mutation leads to abnormality in neuronal migration; however, new research has also revealed that Lis1 plays a crucial role in preserving axonal transport in the adult brain. Another important factor is the p150 Glued, a component of dynactin encoded by the DCTN1 gene. Mutations in this gene are strongly connected to Perry syndrome, an aggressive type of Parkinson’s disease (Moughamian and Holzbaur 2012). One uncommon kind of motor neuron disease called HMN7B (neuropathy, distal hereditary type VIIB) is brought on by a unique mutation within the domain of DCTN1 that results from mutations in the scaffolding proteins and related effector proteins. As exemplified, Rab7, which is a GTPase protein, is attached to the membrane of late-endosomes/ lysosomes and, therefore, is essential in dynein/dynactin motor complex recruitment. Rab7 mutations have also been linked to Charcot-Marie-Tooth syndrome and is demonstrated to interfere with endosome axonal transport in sensory neurons (Zhang et al. 2013; Guedes-Dias et al. 2016). In another system, to coordinate the activity of kinesin/dynein motor complexes, the Huntingtin protein may function as a motor scaffold. Huntingtin’s scaffolding activities are adversely impacted by pathogenic enlargement of the polyQ repeat region, which impedes the axonal transport of a variety of payloads, including auto-phagosomes and mitochondria (Wong and Holzbaur 2014). Lastly, diseases can be brought on by alterations that change microtubule control or structure. For instance, brain abnormalities and neurodevelopmental problems are caused by mutations in different alpha and beta-tubulin isoforms (Guedes-Dias and Holzbaur 2019; Ikenaka et al. 2012). In Table 8.2, various mutations in axonal transport genes are mentioned that show relatedness to the neurological abnormalities.
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Table 8.2 Abnormalities of neurological system and the associated gene mutations in axonal transport Protein complex/gene 1. Kinesin 3/KIF1A 2. Kinesin 3/KIF14 3. Kinesin 1/KIF5A 4. Kinesin 4/KIF21A 5. Dynactin1/P150Glued/ DCTN1 6. Dynein cytoplasmic 1 heavy chain 1/DYNC1H1 7. NudE neurodevelopment protein 1/NDE1 8. α1A-Tubulin/TUBA1A 9. Β-Tubulin class 1/TUBB 10. β2A-Tubulin class IIa/ TUBB2A 11. β3-Tubulin class III/ TUBB3 12. β4B-Tubulin class IVa/ TUBB4A 13. γ1-Tubulin/TUBG1
Disease • Spastic paraplegia • Hereditary sensory neuropathy type IIC (HSN2C) • Meckel syndrome and • Primary microcephaly • Amyotrophic lateral sclerosis (ALS), spastic paraplegia10 (SPG10)/Charcot–Marie–Tooth disease type 2 (CMT2) • Congenital fibrosis of extraocular muscles • Distal hereditary motor neuropathy type VIIB • Spinal muscular atrophy, lower extremity predominant 1 (SMALED1) • Microhydranencephaly (MHAC) • Lissencephaly 3 (LIS3) • Complex cortical dysplasia with other brain malformations 6 • Complex cortical dysplasia with other brain malformations 5 (CDCBM5) • Congenital fibrosis of extraocular muscles 3A (CFEOM3A) • Hypo-myelinating leukodystrophy 6 (HLD6), Torsion dystonia 4 (DYT4) • Complex cortical dysplasia with other brain malformations 4 (CDCBM4)
8.8 Axonal Transport Abnormalities and Related MND Pathogeneses 1. Amyotrophic lateral sclerosis (ALS): ALS is a deadly neurodegenerative condition known to cause a gradual loss of motor neurons. About 90% of ALS cases are sporadic (SALS), with no known genetic abnormality, whereas 10% have familial (FALS) inheritance patterns (Rowland and Shneider 2001; Ince et al. 2011). However, the abnormal pattern of accumulation of neuro-filaments, auto- phagosomes, and damaged mitochondria, found in patients of SALS with motor neuron disease, suggests that axonal transport defects may be implicated in its pathogenesis. Even though the molecular mechanisms causing axonal transport defects are still unknown (Chua et al. 2022). Using laser-captured microdissection and microarray technology, researchers were able to identify the expression of motor neuron-specific gene profiles of patients with SALS (Jiang et al. 2005; Taylor et al. 2002). The findings were further validated by in-situ hybridization and wide-ranging quantitative research efforts. It has been reported that dynactin-1 was significantly downregulated in motor neurons of SALS with dysregulated expressions (Jiang et al. 2007). Moreover, it was also discovered that the
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downregulation of dynactin-1 takes place before the build-up of phosphorylated neuro-filament, another sign of impaired axonal transport and rather an early indicator of neurodegeneration (Nikolsky et al. 2005). 2. Spinal and bulbar muscular atrophy (SBMA): SBMA is also known as Kennedy’s disease, a genetic neurodegenerative condition marked by the loss or injury of bulbar and spinal motor neurons (Kennedy et al. 1968). The amplification of a trinucleotide CAG repeats, which generates a poly-glutamine region in the first exon of the AR (androgen receptor) gene, is the primary genetic abnormality that causes SBMA (Gatchel and Zoghbi 2005). In a study, by blocking transcription factors and coactivators, the resultant mutant AR aggregates in the nucleus and influences the gene expression of a number of genes (Kemp et al. 2011; Katsuno et al. 2006; Sobue et al. 1989). By the activation of JNK (c-Jun N-Terminal Kinases), kinesin-1 heavy chain subunits phosphorylates and leads to inhibition of kinesin-1 activity and poly-glutamine-expanded AR prevents axonal transport (Trojaborg and Wulff 1994). Intriguingly, a research group discovered through testing on transgenic model mice through fluro-gold labeling study that dynactin-1 is downregulated in the SBMA as well as in SALS patients and their retrograde axonal transport was considerably compromised (Monks et al. 2007). Moreover, aberrant neuro-filaments and accumulations of synaptic protein were seen in the distal portion of axons (Feiguin et al. 1994). It has also been discovered that retrograde transport problems were present before MNDs symptoms appeared, making it a point of greater concern. As part of treatment, they were repaired by hormone treatments that stop mutant AR from building up in the nucleus, hence preventing impaired transportation (Malik et al. 2011). 3. Spinal muscular atrophy (SMA): There are three different types of spinal muscular atrophy, including a severe form (type I; Werdnig-Hoffmann disease), an intermediate form (type II), and a juvenile variant (type III; Kugelberg–Welander disease) (Lorson et al. 2010). SMA is an autosomal recessive disease which only affects lower motor neurons (Rochette et al. 2001). SMA is the most common hereditary cause of infantile death in the United States, occurring in 1 in 6000 live births (Feldkötter et al. 2002). The “survival motor neuron 1” gene (SMN1), which is crucial for RNA metabolism, causes SMA upon mutation or deletion (Kong et al. 2009). Pathological alterations at neuromuscular junctions, such as reduced synaptic vesicle density, synaptic transmission issues, and neuro- filament buildup, are brought on by low levels of SMN1 (Lefebvre et al. 1997). Fast anterograde axonal transport appears compromised in SMA, providing the molecular foundation for the synaptic dysfunction (Rose Jr et al. 2008; Dale et al. 2011). 4. Hereditary spastic paraplegias (HSP): These are a diverse set of genetic illnesses defined by the spastic weakening of the lower extremities brought on by retrograde degradation of posterior columns and the corticospinal tracts (Blackstone et al. 2011). Rapid reflexes, extensor plantar reflexes, and urgency in the urination frequently accompany these symptoms. Dependent on the existence of various other neurological characteristics, in addition to spastic paraplegias, this condition is divided into “pure” (uncomplicated) HSP and “complicated”
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Table 8.3 Commonly associated genetic markers and their phenotypic symptoms in MNDs Motor neuron disorder Disease type ALS1 ALS2 ALS8 Lower MND SBMA SPG3 SPG10 SPG4
Genetic marker SOD1 ALS2 VAPB DCTN1 AR ATL1 Kif5A SPAST
Phynotypic symptoms Loss of motor neurons Muscle weakness and paralysis Upper and lower motor disease Impairing retrograde axonal transport Lower motor neuron disorder Progression in HSP Leg spasticity and weakness ATPase dysfunctionality
HSP (Elsayed et al. 2021). Pure HSP is characterized by spastic weakness that is limited to the lower extremities, while complex HSP is characterized by mental retardation, ataxia, extrapyramidal symptoms, visual impairment, or epilepsy (Noreau et al. 2014). Atlastin, spastin, and K1F5A are three of the HSP-causing proteins that control axonal transport. Although KIF5A controls anterograde axonal transport, atlastin and spastin promote vesicle trafficking. Dysfunctionality in any of these proteins strongly contributes towards the occurrence of the HSP (Xia et al. 2003). Additionally, given in Table 8.3 are other commonly studied genes and their significance in several motor neuron diseases.
8.9 Conclusion Axonal transport has a pivotal role in the proper functionality of a human body, as our body is dependent on the signals that the brain receives and transmits back as response to various organs. The division of transport can be anterograde type or retrograde type, and it can also be slow transmission or fast transmission. In this efficient system, the critical genetic markers must function optimally and in a regulated fashion. Any dysfunctionality in the genes that encode factors for a mode of synaptic transmission and axonal transportation has a serious obstructive role on the homeostasis of such proteins. This debilitated system is responsible for the loss of functionality of various protein-coding genes and other important kinases, which ultimately halts the pattern of a regulated signaling cascade. In addition to this, cargos of this system get affected. This leads to the insignificant responsive nature of the neuronal system, hence leading to neurological disorders. Some commonly reported neurological disorders enlisted in such category are motor neuron disorders (ALS, SMA, SBA, and HD). These disorders are responsible for causing serious muscle spasticity, muscle atrophy, and result in the loss of lower and upper motor neurons. This leads to the accumulation of vesicular debris, resulting in neurodegenerative diseases like Parkinson’s and Alzheimer’s diseases. As studying the brain, the system has always been a greater challenge, but the scientific community has always been looking for possible targets and their therapeutic interventions for curing motor neuron disorders. Hence, these biomarkers and the kinetic behavior of
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associated proteins could be exploited as a potential target for designing effective therapeutic strategies for the treatment of these ailments in future.
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9
Alterations in Receptor Genes in Huntington’s Disease Tarun Kumar Suvvari, Ayush Anand, Shivangi Srivastava, and Mainak Bardhan
Abstract
In this chapter, we explored the alterations in receptor genes associated with Huntington’s disease (HD). The dysfunction and composition of receptor genes in HD are investigated, with a specific focus on the role of these genes in the disease and the receptors that are altered. Receptor genes play a crucial role in HD by encoding proteins involved in cellular signal transduction. Dysfunction in these receptors can disrupt normal cellular activities, leading to the characteristic symptoms of HD. Understanding the alterations in receptor genes provides valuable insights into the pathogenesis of HD and offers potential therapeutic targets for the development of effective treatments. To gain a more comprehensive understanding of how alterations in these receptor genes play a role in the development of HD and to devise targeted treatments that can alleviate the devastating consequences of this disorder, further investigation is necessary. Keywords
Huntington’s disease · Receptor genes · Huntingtin gene · Alterations T. K. Suvvari (*) Rangaraya Medical College, Kakinada, India Squad Medicine and Research (SMR), Visakhapatnam, Andhra Pradesh, India A. Anand BP Koirala Institute of Health Sciences, Dharan, Nepal S. Srivastava T.S. Misra Medical College and Hospital, Lucknow, India M. Bardhan ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India Department of Neuro Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_9
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9.1 Introduction Huntington’s disease (HD) is a progressive neurodegenerative disorder (Bates et al. 2015; Walker 2007) with a global incidence of 0.48 cases per 100,000 person-years and a prevalence of 4.88 cases per 100,000 persons (Medina et al. 2022). It is inherited in an autosomal dominant pattern and is caused by “cytosine–adenine–guanine (CAG) trinucleotide repeat expansion in the huntingtin (HTT) gene on the short arm of chromosome 4” (HDCRG 1993). While HD can manifest at any age, it is most commonly observed in middle-aged adults, although onset can occur from childhood to the eighth decade of life (Bates et al. 2015). The classic presentation of HD includes chorea, psychiatric comorbidities, and cognitive decline. A crucial aspect of the diagnostic process is obtaining a detailed medical history, particularly regarding the presence of HD in siblings, parents, or grandparents, which can provide valuable clues for the diagnosis. Genetic testing can be used as a diagnostic or predictive modality (Kremer et al. 1994; MacLeod et al. 2013). Genetic testing for CAG expansion ≥36 repeats is confirmatory in most cases (Kremer et al. 1994). Predictive genetic testing can be done in individuals at high risk for developing HD (MacLeod et al. 2013). Imaging modalities such as magnetic resonance imaging (MRI) and positron emission tomography of the brain can reveal caudate atrophy (Wilson et al. 2018; Feigin et al. 2001). To aid in the diagnosis and treatment of HD, various guidelines are available (Sorbi et al. 2012; Reilmann et al. 2014). The approach to the treatment of HD is mainly symptomatic (Bachoud-Lévi et al. 2019). In addition to pharmacotherapy, physical and occupational therapy in conjunction with palliative care is required.
9.2 Pathogenesis of HD Although the exact mechanisms of pathogenesis in HD are not clearly understood, a few mechanisms pertaining to the therapeutic approach in HD have been explored.
9.2.1 Aggregation of Mutant Huntingtin The mutant huntingtin aggregation occurs through nucleated growth ultimately leading to the formation of an amyloid-like structure (Chen et al. 2002; Chen and Wolynes 2017). However, the evidence behind whether mutant huntingtin aggregation is protective or deleterious has yielded contrasting evidence. In a study by DiFiglia et al. (1997), mutant huntingtin gene was observed to accumulate in neuronal inclusions within the nucleus and dystrophic neurites. These aggregates were primarily found in the cortex and striatum regions, which are known to be affected by HD. Another study conducted by Becher et al. (1998) reported the presence of intranuclear huntingtin aggregates, predominantly in the neocortex. Additionally, intranuclear aggregates were observed in the caudate and putamen nucleus, which are also affected areas in HD. Gutekunst et al. (1999) reported huntingtin aggregates
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mainly in gray matter, primarily in the cytoplasm. These aggregates were also reported in nuclear and perinuclear areas as well as in white matter (Gutekunst et al. 1999). It should be noted that while the aggregates primarily consisted of expanded mutant huntingtin, other proteins, such as ubiquitin, were also identified in intranuclear aggregates (DiFiglia et al. 1997; Becher et al. 1998). These aggregates may also be formed with proteasomes, molecular chaperones, transcription factors, and wild-type huntingtin (Cummings et al. 1998; Warrick et al. 1999; Chen et al. 2002; Chen and Wolynes 2017; DiFiglia et al. 1997; Becher et al. 1998). Becher et al. (1998) found that the length of the expanded NH2-polyglutamine region in huntingtin was related to the degree of huntingtin aggregation. Martindale et al. (1998) reported that increasing the length of polyglutamine can lead to a higher level of cellular toxicity. This indicates that the aggregation of mutant huntingtin might contribute to the harmful effects observed in HD. Interestingly, not all intranuclear HD aggregates necessarily result in cell death induced by Huntington’s disease, there is a possibility for intranuclear HD aggregates to be present without causing cellular demise. Additionally, the studies revealed a potential protective effect of HD aggregates. It was found that these aggregates could lead to improved survival and reduced levels of mutant huntingtin. This indicates that the aggregation of mutant huntingtin might have a beneficial effect in certain contexts (Huang et al. 1998). However, despite these findings, further research is required to fully understand the role of mutant huntingtin aggregation in Huntington’s disease.
9.2.2 Transcriptional Dysregulation in HD The past decade has witnessed growing evidence regarding the role of transcriptional dysregulation in HD. The transcriptional dysregulation can be a result of the interaction of mutant huntingtin with various transcription factors, such as FOX proteins, PGC-1α, and heat shock transcription factors (HSF). FOX proteins are transcription factors that have a pivotal role in neuronal cell growth (Steffan et al. 2000). FOX proteins, such as FOXp1 and FOXp2, can aggregate with mutant huntingtin in mice models and humans (Kazantsev et al. 1999). FOXp1 is selectively expressed in brain regions where mutant huntingtin is located. A transgenic mouse model study reported downregulation of FOXp1 in the cortex and striatum, with normal expression in other brain areas (Busch et al. 2003). Also, the restoration of FOXp1 expression resulted in a neuroprotective effect. Kazantsev et al. (1999) found that FOXp2 downregulation can lead to HD-associated behavioral disorders. These studies reflect that the downregulation of FOX proteins can play a pivotal role in the pathogenesis of HD. However, the role of other FOX proteins, such as FOXp3 and FOXp4, is less known. PGC-1α has a central role in energy homeostasis and regulation of reactive oxygen species metabolism (Martindale et al. 1998). Cui et al. (2006) reported reduced PGC-1α expression in postmortem examination of the striatum of presymptomatic HD patients. A similar finding was observed in a mice model study by Chaturvedi et al. (2010). Both
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studies found that mutant huntingtin led to significant downregulation of PGC-1α expression. The suppression of PGC-1α transcription results from the binding of mutant huntingtin to the promoter and interfering with the cAMP response binding element-binding protein-dependent pathway (Steffan et al. 2000). Additionally, PGC-1α had a protective role against mutant huntingtin-induced neurotoxicity (Arrasate et al. 2004). PGC-1α increases during oxidative stress and plays a central role in the suppression of the development of reactive oxygen species in neural cells, leading to a neuroprotective effect. HSFs are responsible for cellular defense response through the upregulation of heat shock response genes (Pogoda et al. 2021). They play an important role in neural development and function, and shield from proteotoxicity and cell death. Riva et al. (2012) found that mutant huntingtin can significantly downregulate the stress response regulated by HSF-1, which can contribute towards protein misfolding and aggregation (Pogoda et al. 2021; Hachigian et al. 2017). Over a long time, this may lead to significant neuronal cell death, ultimately leading to neurodegenerative diseases, such as HD. HSF-1 may also be related to the formation and function of excitatory synapses, further research is required to delineate the exact association. NF-κB is a protein complex that acts as a transcription factor in a variety of pathways and is found in all cells of the nervous system pathway (Steffan et al. 2000; Mattson and Meffert 2006). The exact mechanism of the interaction of mutant huntingtin with NF-κB is not known. In astrocytes, the interaction of mutant huntingtin with NF-κB or the absence of wild-type huntingtin leads to hyperactivation of the immune system, exhibiting a neurotoxic effect (Titus et al. 2017). Hence, lowering of mutant huntingtin can repress immune-mediated effects (Puigserver et al. 1998; Träger et al. 2014). RE1 silencing transcription factor (REST) was earlier believed to have a role in embryogenesis only (St-Pierre et al. 2006). McGann et al. (2021) revealed the occurrence of REST in mature neurons in the hippocampus of mice and humans. Cheng et al. (2022) reported that REST acts as a suppressor of the CNS regeneration pathway. In contrast, McGann et al. (2021) suggested that glial REST may have a potential role in neuroprotection by suppressing immune and inflammatory pathways. Despite the current evidence, there is a need for further studies to exactly identify the role of REST in aging.
9.2.3 Epigenetic and Noncoding RNAs in HD In the past decade, extensive research has been undertaken to identify the epigenetic alterations in HD. Ng et al. (2013) reported major DNA methylation changes in the striatum in HD, particularly in CpG-poor regions of the genome. Also, the majority of the dysregulated genes in the mutant huntingtin-expression cell line exhibited methylated DNA. Furthermore, AP-1 and SOX-2 were identified as potential transcriptional regulators for methylation. This study showed the role of epigenetics in the transcriptional regulation of HD. Lu et al. (2020) reported a significant
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relationship between HD mutation status and 33CpG sites. Also, motor progression in HD cases showed a significant relation with methylation levels in mammals. Another study supported the use of DNA methylation level as an epigenetic clock (Lu et al. 2020). Horvath (2013) conducted a study revealing a significant link between the onset age of motor symptoms in HD and the acceleration of epigenetic aging, particularly in the frontal lobe, cingulate gyrus, and parietal lobe (Horvath et al. 2016). Furthermore, they observed a positive relationship between the length of CAG repeats and the severity of HD, while also noting a negative correlation between CAG length and the age of symptom onset (Ghafouri-Fard et al. 2022). Adenosine A2A receptor expression is significantly reduced in HD and is associated with a reduced level of 5hmC (Villar-Menéndez et al. 2013). This points towards DNA methylation as a potential pathway. Gutierrez et al. (2019) found that DNA methylation at BDNF promoter IV was significantly increased, reflecting its role as a biomarker in HD. Overall, these pieces of evidence point toward the significant role of epigenetics in HD. Non-coding RNAs can also influence gene expression in HD. Various miRNAs such as miR-124, miR-128a, miR-34a, miR-10, miR-22, mir-9, miR-214, miR-196a, miR-10b-5p, etc. have been studied, so far (Packer et al. 2008; Martí et al. 2010). Johnson et al. (2008) reported dysregulation of certain micro RNAs (miRNAs) in HD mice and humans, leading to increased levels of target messenger RNAs. Similarly, Packer et al. (2008) also reported a decreased level of miRNAs in the cortex of HD patients. Studies also suggested the role of REST and p53 in the downregulation of miRNAs in HD (Martí et al. 2010). Another interesting observation is the occurrence of huntingtin in RNA structures. This points towards the possibility of the influence of huntingtin on protein expression. However, further investigation is warranted to establish the association. A few long non-coding RNAs, such as DNM30S, NEAT 1, Meg3, and Abhd11os, have been reported to be dysregulated in HD (Savas et al. 2008). DNM30S downregulation contributed to reduced aggregate formation, apoptosis, and increased levels of reactive oxygen species (Dong and Cong 2021). Sunwoo et al. (2017) reported that NEAT-1 transfected neuronal cells had increased survival under oxidative stress, pointing towards a neuroprotective role of NEAT-1 in HD. Another study reported that the knockdown of mutant huntingtin led to the restoration of the NEAT-1 level (Cheng et al. 2018). This pointed toward mHTT-dependent regulation of NEAT-1. Chanda et al. (2018) found that Meg3 and NEAT-1 downregulation can result in a reduced level of HD aggregates and Tp53 expression. Another long-coding RNA, Abhd11os, exhibited a neuroprotective effect when upregulated (Francelle et al. 2015). All these pieces of evidence point toward a significant role of non-coding RNAs in the pathogenesis of HD.
9.2.4 Role of Ubiquitin–Proteasome System and Autophagy– Lysosome System in HD Ubiquitin–proteasome system (UPS) and autophagy–lysosome system are major protein degradation systems concerned with the degradation of wild-type and
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mutant huntingtin, respectively (Savas et al. 2010; Ratovitski et al. 2012). A lot of researches have been done to study the role of these protein-degrading systems in Huntington’s disease. Kegel et al. (2000) found increased autophagosomes in HD and speculated that HD aggregates might lead to the activation of the lysosomal system and autophagy. Bence et al. (2001) found that the expression of huntingtin protein along with another aggregation-prone protein led to a complete shutdown of UPS function. Another study found that the use of proteasome inhibitors led to the increased aggregate formation of huntingtin protein with 60 glutamine repeats (Jana et al. 2001; Jimenez-Sanchez et al. 2017). Also, aggregated proteins showed resistance to the degradation by UPS. These studies pointed toward a direct relationship between aggregate formation and UPS. However, Bett et al. (2009) showed that protein aggregates do not downregulate the UPS directly. Rather, there is a possibility that aggregates can downregulate UPS function by regulating the function and distribution of UPS modulators. Other studies suggest that HD aggregates may not lead to a complete blockage of the UPS function (Jana et al. 2001; Bett et al. 2009). Also, proteasomes can completely degrade polyQ sequences with no inhibition of proteasomal function. These pieces of evidence reflect a need for further research in this area.
9.2.5 Synaptic Plasticity and Neuronal Hemostasis in HD Aberrant synaptic plasticity and altered neuronal hemostasis are early pathogenic processes in HD. Huntingtin acts as a scaffold connecting the microtubules, cargoes, and motor proteins (Bett et al. 2009). Huntingtin-associated protein1 mediates the trafficking of vesicles (Milnerwood et al. 2006). However, HAP1 is impaired in HD. In addition to transcriptional dysregulation already discussed in this review, studies have shown that mutant huntingtin protein aggregation in cytoplasm results in microtubule disruption and trafficking defects, resulting in mitochondrial dysfunction, ultimately leading to neuronal death (Gomez-Pastor et al. 2017; Caviston et al. 2007). This explains the reason behind synaptic plasticity and altered neuronal hemostasis.
9.2.6 Cell-to-Cell Transmission of HD Aggregates Recent studies have shown that proteins may get transmitted from cell to cell, spreading the HD to various regions of the brain. Mutant huntingtin leads to an increased number of transfer channels between cells, such as prions, leading to an improved and faster transfer (McGuire et al. 2006; Lee et al. 2004). This might play a role in the early development of HD, and its use as therapeutic control strategy should be explored.
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9.2.7 Astrocyte and Microglial Dysfunction in HD Astrocytes are glial cells that protect the neurons by uptake of extracellular glutamate, thus preventing excitotoxicity. The presence of mutant huntingtin in astrocytes downregulates the expression of glutamate transporter (Bradford et al. 2009). Also, an increase in detrimental neurological symptom profiles in the presence of mutant huntingtin in glial cells has been reported (Bradford et al. 2010). This reveals an important role of astrocytes in HD pathogenesis.
9.3 Genetics of HD Understanding the genetics of HD is essential for comprehending the inheritance pattern and the underlying mechanisms of the disease. The huntingtin gene is located on chromosome 4 and encodes a protein called huntingtin. In individuals with HD, there is an abnormal expansion of a trinucleotide repeat sequence, specifically CAG, within the HTT gene. The number of CAG repeats in the gene determines whether an individual will develop HD, as well as the age of onset and severity of the symptoms. HD follows an autosomal dominant inheritance pattern. This means that if an individual inherits one copy of the mutated HTT gene from an affected parent, they have a 50% chance of developing the disease themselves. The presence of an expanded CAG repeat sequence within the HTT gene causes the production of a mutant huntingtin protein (mHTT), which accumulates in neurons and disrupts their normal functioning, ultimately leading to cell death. The number of CAG repeats within the HTT gene is correlated with the age of symptom onset and the severity of symptoms experienced in Huntington’s disease (HD). Individuals with 36 or fewer CAG repeats typically do not develop the disease, while those with 40 or more repeats will usually exhibit symptoms of HD in their lifetime. Intermediate repeat lengths (37–39) may result in reduced penetrance, where some individuals may or may not develop symptoms (Myers 2004). Anticipation is another important aspect of HD genetics. Anticipation refers to the phenomenon where the number of CAG repeats expands in subsequent generations. This expansion often leads to earlier onset and increased severity of symptoms. It is believed to be caused by errors during DNA replication, leading to an increase in the number of repeats (Myers 2004).
9.3.1 Composition and Function of Wild Type of Huntingtin Gene The Huntingtin protein is encoded by the HTT gene. The huntingtin gene is a large gene that is located on the short arm of chromosome number 4. The wild-type (normal) huntingtin gene has a concatenation of approximately 67 exons and stretches across 180 kb of DNA, carrying 300,000 base pairs (O’Regan et al. 2020; Harding et al. 2019). The sequence of the wild-type huntingtin gene diverges
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marginally among individuals, but the overall structure and function of the gene are conserved (Reiner et al. 2003). The gene is transcribed into a large mRNA molecule that is processed and translated into the huntingtin protein, which is approximately 3500 amino acids long (Reiner et al. 2003). In huntingtin protein (encoded by wildtype huntingtin gene), the glutamine residues protract out near its N-terminus, and amplification of this repeat region is the fundamental cause of neurodegenerative diseases like Huntington’s, a neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms (O’Regan et al. 2020; Arribat et al. 2013). The composition of the wild-type huntingtin gene includes several regulatory regions, like promoters and enhancers, that control the expression of the gene in various tissues and developmental stages. In addition, the gene contains manifold alternative splicing sites that allow for generating different isoforms of the huntingtin protein with well-defined functions (Déglon 2017; Landles and Bates 2004). An overview of HTT gene and HTT protein is described in Figs. 9.1 and 9.2. The huntingtin protein is involved in various cellular functions in the human body. The specific role of the huntingtin protein has not been fully elucidated, but it is known to be involved in multiple cellular mechanisms, including the movement of substances within cells, the control of gene activity, and the regulation of programmed cell death (apoptosis).
Fig. 9.1 Location of HTT gene on chromosome 4 and the haplotypes which are targeted to produce a mutant form of HTT
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Fig. 9.2 Comparison of post-translational products in normal HTT and mutant HTT. In normal HTT, nontoxic fragments are produced which enables the N-terminal to attach with the C-terminal. Whereas, in mutant HTT, toxic fragments are produced which does not the N-terminal attachment with a complimentary site
1. Intracellular trafficking: The huntingtin protein helps in the transport of various cellular cargo, like vesicles and organelles, along microtubules, which ensures the delivery of essential molecules to their appropriate locations within the cell, thus helping the cell to carry out its normal functioning. 2. Transcriptional regulation: Huntingtin regulates the expression of various genes by interacting with transcriptional factors like CBP (CREB-binding protein) and SP1. Thus, huntingtin may have a role in gene expression and cellular differentiation. 3. Apoptosis: Huntingtin has been shown to play a role in the regulation of apoptosis, or programmed cell death. Studies suggest that huntingtin may act as a pro-apoptotic factor, promoting cell death in response to certain stimuli. 4. Neuroprotection: Recent studies have suggested that the huntingtin protein may play a role in protecting neurons from oxidative stress and other types of cellular damage. This can explain why the loss of huntingtin function is associated with the development of neurodegenerative diseases, like Huntington’s disease. Overall, the function of the wild-type huntingtin gene appears to be essential for normal cellular function, including intracellular trafficking, transcriptional regulation, and apoptosis. It is still not fully understood, but ongoing research is shedding light on its various roles in the human body.
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9.4 Function and Composition of Receptor Genes in HD One of the key features of HD is the selective loss of neurons in specific regions of the brain, including the striatum, which is involved in motor control and coordination (Jurcau 2022). Recent research has identified alterations in several receptor genes in HD, which may contribute to the pathogenesis of the disease. Receptor genes are important because they encode proteins that are involved in signal transduction between cells. These proteins can bind to specific molecules, such as neurotransmitters or hormones, and initiate a signaling cascade that leads to changes in the activity of the cell (Jurcau 2022).
9.4.1 Role of Receptor Genes in HD Several receptor genes have been implicated in the development and progression of HD. For example, the dopamine D2 receptor gene (DRD2) is involved in the regulation of motor function and reward-related behavior. Alterations in this gene have been associated with the development of motor symptoms in HD, including chorea (involuntary movements) and bradykinesia (slowness of movement) (Crook and Housman 2012). In addition to dopamine receptors, alterations in other receptor genes have also been identified in HD. For example, the N-methyl-d-aspartate (NMDA) receptor gene (GRIN2B) is involved in the regulation of synaptic plasticity and learning and memory. Alterations in this gene have been associated with cognitive impairment in HD (Saft et al. 2011). Another receptor gene that has been implicated in HD is the serotonin receptor 5-HT1A gene (HTR1A). Serotonin is a neurotransmitter that is involved in the regulation of mood, anxiety, and cognition. Alterations in the HTR1A gene have been associated with anxiety and depression in HD patients (Pang et al. 2009; Yohrling et al. 2002).
9.4.2 Receptor Genes Altered in HD One of the receptor genes that has received a lot of attention in HD research is the metabotropic glutamate receptor 5 gene (GRM5). This receptor is involved in the regulation of synaptic plasticity and is expressed at high levels in the striatum. Alterations in GRM5 have been associated with the development of motor and cognitive symptoms in HD (Ribeiro et al. 2014; Santos et al. 2022). Studies have shown that mHTT can interact with GRM5 and disrupt its normal function. This can lead to changes in the activity of downstream signaling pathways, which can contribute to the pathogenesis of HD. In addition, drugs that target GRM5 have shown promise in preclinical studies as potential treatments for HD (Ribeiro et al. 2014; Santos et al. 2022). Another receptor gene that has been implicated in HD is the cannabinoid receptor 1 gene (CNR1). The endocannabinoid system is involved in the regulation of a variety of physiological processes, including pain, mood, and appetite. Alterations in CNR1 have been associated with changes in the activity of this
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system and may contribute to the development of neuropsychiatric symptoms in HD (Zou and Kumar 2018). Similarly, alterations in the insulin-like growth factor 1 receptor gene (IGF1R) have also been identified in HD (Kloster et al. 2013). IGF1 is involved in the regulation of cell growth and survival, and alterations in this pathway have been implicated in many neurodegenerative disorders, including HD. Studies have shown that activation of the IGF1 pathway can protect against neuronal death in HD, suggesting that drugs that target this pathway may have therapeutic potential (García-Huerta et al. 2020) (Table 9.1). Table 9.1 Various receptors associated with Huntington’s disease and their characteristics Receptors Glutamate receptors
Characteristics Glutamate is the main excitatory neurotransmitter in the brain, and its receptors play a key role in HD pathology
Sub-receptors NMDA receptor
AMPA receptor
Kainate receptor
GABA receptors
GABA is the main inhibitory neurotransmitter in the brain, and its receptors play a key role in HD pathology
GABAA receptor
GABAB receptor
Characteristics NMDA receptors are important for learning and memory, and their dysfunction has been linked to HD. Studies have shown that NMDA receptor antagonists can protect against neuronal damage in HD animal models AMPA receptors play a crucial role in synaptic plasticity, contributing significantly to the processes of learning and memory. Alterations in AMPA receptor function have been observed in HD, which may contribute to cognitive dysfunction in the disease Kainate receptors are involved in synaptic transmission and are expressed in various brain regions. Research findings have indicated that the impaired functioning of kainate receptors could potentially play a role in the development of motor symptoms associated with HD GABAA receptors are responsible for regulating the excitability of neurons and are found in different regions of the brain. Disruptions in GABAA receptor activity could potentially play a role in the cognitive and motor symptoms observed in HD GABAB receptors play a crucial role in modulating synaptic transmission and are expressed in different areas of the brain. Abnormalities in GABAB receptor function could potentially contribute to the motor symptoms associated with HD (continued)
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Table 9.1 (continued) Receptors Dopamine receptors
Serotonin receptors
Characteristics Dopamine is a neurotransmitter that plays a role in reward and motivation, as well as in motor control
Sub-receptors D1 receptor
Serotonin is a neurotransmitter that plays a role in mood, appetite, and sleep
5-HT1A receptor
D2 receptor
5-HT2A receptor
Other receptor genes
Adenosine A2A receptor
Cannabinoid CB1 receptor
Nicotinic acetylcholine receptor
Characteristics D1 receptors are involved in the regulation of motor activity and reward pathways. Studies have suggested that alterations in D1 receptor function may contribute to the motor symptoms of HD D2 receptors are involved in the regulation of motor activity and reward pathways. Studies have shown that D2 receptor agonists can improve motor function in HD animal models 5-HT1A receptors are involved in the regulation of mood and anxiety. Studies have suggested that alterations in 5-HT1A receptor function may contribute to the psychiatric symptoms of HD 5-HT2A receptors are involved in the regulation of mood, perception, and cognition. Studies have shown that alterations in 5-HT2A receptor function may contribute to the cognitive symptoms of HD Adenosine A2A receptors are involved in the regulation of dopamine transmission and are expressed in the striatum. Studies have suggested that adenosine A2A receptor antagonists may have therapeutic potential in HD Cannabinoid CB1 receptors participate in the regulation of neuronal excitability and are found in different regions of the brain. Changes in CB1 receptor activity might be implicated in the motor symptoms associated with HD. In individuals with HD, the diminished function of CB1 receptors could potentially contribute to the excessive stimulation of striatal neurons, resulting in motor dysfunction Nicotinic acetylcholine receptors are involved in the regulation of cognitive function, motor control, and reward pathways. Studies have suggested that alterations in nicotinic acetylcholine receptor function may contribute to the cognitive and motor symptoms of HD
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The molecular mechanisms underlying HD pathology are complex and involve alterations in various cellular processes, including protein degradation, mitochondrial function, and transcriptional regulation. Receptor genes play a crucial role in HD pathology by regulating neurotransmission and signal transduction pathways in the brain. Glutamate receptors are the most abundant receptors in the brain and are involved in mediating excitatory neurotransmission. In HD, the dysfunction of glutamate receptors contributes to the pathophysiology of the disease. The N-methyl-d-aspartate (NMDA) receptor is a subtype of glutamate receptor that is essential for synaptic plasticity, learning, and memory (Ribeiro et al. 2014). Studies have suggested that alterations in NMDA receptor function may contribute to the cognitive and psychiatric symptoms of HD. In HD animal models, the expression of NMDA receptor subunits is decreased in the striatum, and pharmacological modulation of NMDA receptor activity can improve motor function and reduce neuronal damage in HD (Fan and Raymond 2007). Similarly, the alphaamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and the kainate receptor, two other subtypes of glutamate receptor, are also involved in HD pathology. Alterations in the expression and function of AMPA and kainate receptors have been observed in HD, and pharmacological modulation of these receptors can improve motor function and delay disease progression (Wagster et al. 1994). GABA receptors are the most abundant inhibitory receptors in the brain and play a crucial role in the regulation of neuronal excitability. The GABA(A) receptor functions as an ion channel activated by ligands and plays a crucial role in facilitating rapid inhibitory neurotransmission. On the other hand, the GABA(B) receptor acts as a G protein-coupled receptor responsible for facilitating slower inhibitory neurotransmission. So, changes in GABA receptor function are implicated in the manifestation of both motor and psychiatric symptoms associated with the condition. In HD animal models, the expression of GABA(A) receptor subunits is decreased in the striatum, and pharmacological modulation of GABA(A) receptor activity can improve motor function and reduce neuronal damage. Similarly, alterations in the expression and function of the GABA(B) receptor have been observed in HD, and pharmacological modulation of GABA(B) receptor activity can improve motor function and reduce anxiety-like behavior in HD (Hsu et al. 2018). Dopamine receptors are involved in the regulation of movement, motivation, and reward pathways in the brain. In HD, alterations in dopamine receptor function contribute to the motor and psychiatric symptoms of the disease. The dopamine D1 receptor and D2 receptor are two subtypes of dopamine receptors that have opposite effects on motor function. The D1 receptor is involved in the facilitation of movement, while the D2 receptor is involved in the inhibition of movement. In HD animal models, the expression of D1 and D2 receptor subtypes is altered in the striatum, and pharmacological modulation of dopamine receptor activity can improve motor function and reduce neuronal damage in HD (Crook and Housman 2012). Serotonin receptors are involved in the regulation of mood, anxiety, and aggression in the brain. In HD, alterations in serotonin receptor function contribute to the psychiatric symptoms of the disease. The 5-HT1A receptor and 5-HT2A receptor are two subtypes of serotonin
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receptor that are involved in the regulation of mood and anxiety. In HD animal models, alterations in the expression and function of these receptors have been observed, and pharmacological modulation of serotonin receptor activity can improve anxiety-like behavior and reduce depressive-like behavior in HD. Adenosine A2A receptor is a G protein-coupled receptor that is highly expressed in the striatum and is involved in the regulation of neurotransmitter release and signal transduction. In HD, alterations in adenosine A2A receptor function contribute to the motor and psychiatric symptoms of the disease. In HD animal models, the expression of adenosine A2A receptor is increased in the striatum, and pharmacological modulation of adenosine A2A receptor activity can improve motor function and reduce neuronal damage in HD (Pang et al. 2009). Cannabinoid CB1 receptor is a G protein-coupled receptor that is highly expressed in the striatum and is involved in the regulation of neurotransmitter release and signal transduction. In HD, alterations in cannabinoid CB1 receptor function contribute to the motor and psychiatric symptoms of the disease. In HD animal models, the expression of cannabinoid CB1 receptor is decreased in the striatum, and pharmacological modulation of cannabinoid CB1 receptor activity can improve motor function and reduce neuronal damage in HD (Zou and Kumar 2018). In addition to these receptor genes, other receptor genes are also involved in HD pathology. The nicotinic acetylcholine receptor is involved in the regulation of cognitive function and is altered in HD. Alterations in the expression and function of this receptor have been observed in HD, and pharmacological modulation of nicotinic acetylcholine receptor activity can improve cognitive function in HD (Simpson et al. 2021).
9.5 Cellular Location of HD Receptor Gene Products 9.5.1 The Expression of HD Receptor Genes in the Brain The HD receptors are expressed in distinct regions of the brain, including the basal ganglia, the prefrontal cortex, the hippocampus, and the amygdala. The basal ganglia are enmeshed in the actuation of movement, and their dysfunction is associated with movement disorders such as HD (Mulgrave et al. 2023). The prefrontal cortex is involved in eclecticism, operant memory, and assiduities, while the hippocampus is involved in erudition and memory. The amygdala partakes in emotion and motivation (Lo and Hughes 2011). The countenance of the HD receptor gene is superintended by various factors, including neurotransmitters, hormones, and environmental stimuli. For example, dopamine, a neurotransmitter that is involved in accolades and inducement, can upregulate the expression of the HD receptor gene. Metamorphosis in the expression of the HD receptor gene has been implicated in various neuropsychiatric disorders, including schizophrenia, depression, and addiction. Therefore, understanding the regulation of HD receptor expression in the brain may have crucial connotations for panacea in the development of new treatments for these disorders.
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9.5.2 The Location and Distribution of Gene Products in HD The mutant huntingtin protein (brought out by mutation in the huntingtin gene) is expressed throughout the body, but it has a particular brunt on the brain, leading to the characteristic symptoms of the disease. In the brain, the mutant huntingtin protein has a scopious distribution, affecting many different cell types and regions. It is particularly concentrated in the striatum, which is part of the basal ganglia and plays a pivotal role in movement control. The mutant huntingtin protein accumulates in the striatal neurons, leading to their dysfunction and eventual death (Jurcau 2022; Lo and Hughes 2011). The mutant huntingtin protein affects other distinguishable regions of the brain, including the cerebral cortex, hippocampus, and thalamus. It disrupts normal cellular processes and leads to the formation of protein aggregates and neuronal death. The distribution of the mutant huntingtin protein in the brain is thought to be responsible for the wide range of symptoms observed in HD, including movement disorders, cognitive impairment, and psychiatric symptoms. Understanding the location and distribution of gene products in HD is essential for developing effective treatments for this cataclysmic disease. Figure 9.3 depicts the anatomical presentation of the distribution of HD receptor genes in the brain and sequelae of HD receptor regulation and the effects of mutation of HD receptor gene.
Fig. 9.3 Anatomical presentation of the distribution of HD receptor genes in the brain and sequelae of HD receptor regulation and the effects of mutation of HD receptor gene
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9.6 Genetic Modifiers in HD 9.6.1 The Influence of Genetic Modifiers on HD Pathogenesis Genetic modifiers are variations in other genes that can transpose the accouterments of the primary mutation and either accelerate or delay the onset of symptoms or alter the severity of the disease, even those with the same mutation. Umpteen genetic modifiers have been identified in HD, including variations in genes that are involved in DNA repair, oxidative stress response, and immune system function. For example, variations in the gene encoding the protein apolipoprotein E (APOE) have been ascendant for the age of onset and rate of progression of HD. People with the APOE4 variant tend to have an expeditious onset and faster disease progression, while those with the APOE2 variant may have a later onset and slower concatenation (Tshilenge et al. 2023; Birajdar et al. 2023). Another genetic modifier that has been studied in HD is the gene encoding the protein brain-derived neurotrophic factor (BDNF). Variations in this gene have been found to affect the severity of HD symptoms, with higher levels of BDNF syndicated with milder symptoms. One example of a genetic modifier is the CAG repeat length. The number of CAG repeats in the Huntingtin gene directly correlates with the age at which symptoms first appear and the severity of HD. Longer repeats are associated with earlier onset and more pronounced symptoms (Birajdar et al. 2023). However, other genes, such as DNA repair genes, can affect the rate of expansion of the CAG repeat, which can in turn influence the age of onset and solemnity of HD. Another genetic modifier includes variation in the genes encoding the proteins dopamine receptor D2, insulin-like growth factor 1, and superoxide dismutase 1. One example of a genetic modifier is the CAG repeat length. The length of the CAG repeat in the huntingtin gene is directly related to the age of onset and severity of HD, with longer repeats leading to the earlier onset and more severe symptoms. However, other genes, such as DNA repair genes, can affect the rate of expansion of the CAG repeat, which can in turn influence the age of onset and severity of HD (Fakhri et al. 2022). Overall, the influence of genetic modifiers on HD pathogenesis is complex and multifarious. Further research is portentous in fully understanding the mechanisms by which these modifiers interact with the primary mutation and identifying potential therapeutic targets for the treatment of HD.
9.6.2 Identification of Genetic Modifiers Identification of genetic modifiers in HD is a Daedalian area of ongoing research. Following are the propositions used by scientists to deduce the genetic modifiers: 1. Genome-wide association studies (GWAS): GWAS are studies that catechize for genetic variations, across the entire genome, that are associated with a particular disease or trait. Several GWAS studies have been conducted in HD to
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3.
4. 5.
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identify genetic modifiers. For example, a 2015 study identified several genetic variants associated with the age of onset of HD (Valor 2023). Candidate gene studies: Candidate gene studies focus on specific genes that are known to be involved in biological pathways relevant to HD. These studies can be advantageous to identify genetic modifiers that are vehemently associated with the disease. For example, a 2013 study found that variations in the DNA repair gene MLH1 were associated with the age of onset of HD (Valor 2023; Morena et al. 2023). Animal models: Considering mice that schlep the mutant huntingtin gene as an exemplification, the effects of genetic modifiers can be studied. By manipulating genes in these animals and surveilling how they affect disease progression, scientists can identify genes that modify the effects of the mutant huntingtin protein (Srinageshwar et al. 2023). Functional genomics: This approach involves studying the raison d’être of genes and proteins in cells and tissues affected by HD (Khan et al. 2020). Multi-omics approaches: This involves integrating data from multiple sources, such as genomics, transcriptomics, and proteomics, to identify genetic modifiers in HD (Khan et al. 2020).
The amalgamation of the above-stated approaches provides optimism to develop targeted therapies that can modify the effects of the mutant huntingtin protein and improve the outcome for individuals with HD (Irfan et al. 2022).
9.7 Conclusion In conclusion, the alterations in receptor genes in HD shed light on the intricate molecular mechanisms underlying the pathogenesis of this devastating neurodegenerative disorder. The investigation of receptor genes and their dysregulation in HD has provided valuable insights into the role of these genes in the disease progression and the potential therapeutic targets they represent. Understanding the genetic basis of HD has enabled genetic testing and counseling, offering valuable information for affected individuals and their families. The identified alterations in receptor genes highlighted the broad impact of HD on neurotransmitter systems. These alterations contribute to the motor, cognitive, and neuropsychiatric symptoms observed in HD patients. Moreover, the identification of genetic modifiers in HD has unveiled the complexity of the disease and the potential influence of additional genes on its manifestation and progression.
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Genetic Modulators in Amyotrophic Lateral Sclerosis
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Babita, Sonal Gaur, Anil Kumar Mavi, and Harsh Vardhan
Abstract
Amyotrophic lateral sclerosis (ALS) is known as one of the fatal diseases among the neurodegenerative disorders. It is characterized by the progressive loss of motor neurons in the cortical, spinal cord, and brainstem regions. This neuronal death leads to paralysis and, in later stages, respiratory failure, often resulting in death. The incidence of ALS is relatively low, with around 1–2 people approx. per 100,000 annually and life expectancy for patients diagnosed is very short, about 3–5 years, as the disease progresses rapidly. ALS is categorized into two forms: familial and sporadic (SALS), with SALS being the most common. Almost 90% of cases are diagnosed without any prior family history of ALS whereas in the less frequent cases up to 10% of patients have familial forms (FALS) of ALS that are mostly found inherited in autosomal dominant patterns. The researchers have identified multiple factors contributing to the development of ALS, including defects in the metabolism of RNA and DNA, disturbance in DNA repair mechanism, protein homeostasis dysfunction, damage in nucleocytoplasmic transport, oxidative stress (OS), excitotoxicity, axonal transport alteraBabita (*) Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India S. Gaur Department of Opthalmology, Medical University of South Carolina, Charleston, South Carolina, USA A. K. Mavi Department of Botany & Life Science, Sri Aurobindo College, University of Delhi, Delhi, India H. Vardhan Department of Pulmonary Medicine, All India Institute of Medical Science, Jodhpur, Rajasthan, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_10
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tion, neuroinflammation, mutation, and nonneuronal cells are also responsible for neurodegeneration. Despite the identification of several genetic factors associated with ALS, the specific mechanism underlying the disease progression remain unclear. Currently, the available treatment strategies are only symptomatic. Hence, further research is required to know the exact mechanism of pathogenesis of the disease. This chapter highlights various genetic modulators and other factors affecting ALS, apart from a mutation in SOD1, several other genes are also discussed as causative factors. Keywords
Neurodegenerative disease · Genetic modulators · Gene mutation · Pharmacotherapy
Abbreviations ALS Amyotrophic lateral sclerosis ALSFRS-R ALS Functional Rating Scale-Revised CNS Central nervous system CSF Cerebrospinal fluid EMG Electromyography FALS Familial forms FUS Fused in sarcoma LMNs Lower MNs MNs Motor neurons MRS Magnetic resonance spectroscopy MUNIX Motor neuron number index NAA N-acetyl aspartate NFL Neurofilament light PET Positron emission tomography RNA Ribonucleic acid SALS Sporadic form SOD2 Superoxide dismutase 2 TARDBP TAR DNA-binding protein gene UMNs Upper MNs
10.1 Introduction Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease that primarily affects the motor neurons (MNs) in the spinal cord and brain of adults. It is known as Lou Gehrig’s disease, characterized by muscle weakness, eventually promoting paralysis, which often progresses toward other parts of the body and may
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cause respiratory muscle failure, finally death due to progressive degeneration of upper–lower MNs. The ALS disease progressed rapidly as a result, limiting the survival time 2–5 years after symptom onset. ALS was first observed by the French neurologist Jean-Martin Charcot in 1869. It gained wider recognition when the famous baseball player Lou Gehrig was diagnosed with the condition in 1939 (Couratier et al. 2016). In the United States, approximately 5000 new cases of ALS are diagnosed annually, and it is estimated that around 20,000 Americans are currently living with the disease. It is considered rare; its reported incidence is about 1–2 cases per 100,000 people every year. The disease affects both genders, with a slightly higher incidence observed in men. While most of ALS cases are sporadic, meaning they occur without any known family history of the disease, about 10% are inherited and linked to mutations in various genes implicated in the pathophysiology of the disease (Traxinger et al. 2013; Longinetti and Fang 2019). The disease typically manifests between the ages of 40 and 70 years, but it can affect individuals of any age. The early symptoms of ALS are often subtle and challenging to diagnose, leading to underdiagnosed cases and sometimes misdiagnoses with other conditions. The early symptoms of ALS include muscle weakness, primarily starting in the limbs, along with muscle cramps, twitching, or stiffness (Ryan et al. 2019). In ALS, the atrophy and muscle weakness become more noticeable as the disease progresses, making everyday tasks such as walking, speaking, and swallowing gradually difficult. The muscle atrophy causes respiratory failure in the advanced stages of the disease. ALS patient’s experience cognitive and behavioral changes in advanced stages of disease, including problems with memory, decision-making, and language, all of which result from the progressive degeneration of MNs in the brainstem, cortex, and spinal cord. Though the subsequent progression of this disease is highly irregular, the initial affected body parts are typically the lower and upper limbs or the bulbar musculature. Bulbar onset cases, found in approx. 25% of patients, involve the facial, mouth, and throat muscles. In rare instances (around 5% of cases), the muscles of the body trunk are affected first. Nevertheless, many patients retain eye movements even in later stages, while control over the sphincter and other muscles may be affected as well, indicating the heightened vulnerability of MNs in ALS (Tan et al. 2017). Despite extensive research, the actual causative factors of ALS remain unknown. However, there is growing evidence pointing to the crucial role of genetic factors in disease pathogenesis. In this context, more than 30 gene associations have been identified in this disease, and mutations in these genes can accelerate defects in various cellular processes, including RNA processing, degradation of protein, and transportation of molecules within cells. Such defects in cellular functioning can finally lead to degeneration of MNs and progressive weakness in muscles of the body. The highly mutated gene is C9orf72 gene which accounts for approx. 40% of cases of familial ALS. Other gene mutations have also been indicated in ALS like SOD1, TARDBP, and FUS. Further some researchers reported that inherited cases account for approx. 10% of all ALS cases and 20% of cases occurred due to mutation in SOD1 gene. Though there is no confirmatory test to diagnose, yet various tests can be used to rule out other diseases to confirm the ALS diagnosis. Therefore, the diagnosis of a disease is done by combining various
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test results and clinical symptoms earlier. The tests for ALS diagnosis may include electromyography (EMG) which measures the electrical activity of muscles, measure nerve transmission signals by nerve conduction studies and other tests, including imaging tests such as CT or MRI scans (Traxinger et al. 2013). This chapter highlights various factors related to ALS such as molecular sub-classification based on genetics and pathophysiology of disease. This review discusses various genetic factors responsible for ALS that can be promising for new drug discovery. Hence, clarity in disease pathogenesis mechanisms and several therapeutic targets can accelerate the development of effective diagnostic measures as well as treatment for this disease.
10.2 Genetic Modulators 10.2.1 SOD1 Gene The first gene investigated in correlation with ALS was SOD1 by Rosen et al. (1993). It is one of the three superoxide dismutase enzymes found in humans. SOD1 gene generates 153 amino acid metalloenzyme proteins to bind copper and zinc, creating a highly stable homodimer. SOD1 dimer is present in the intermembrane space of mitochondria and cytosol. This enzyme protects against OS by the dismutation of free radicals, generated during cellular respiration. It is responsible for 15–30% of fALS and less than 2% of sALS cases (Zou et al. 2013). Variations in SOD1 linked to a reduction in enzyme activity by 50–80%, initially in ALS. However, disease severity is not associated with dismutase activity. The conformational and functional changes occur after mutations in SOD1 gene that may cause toxicity through various mechanisms such as OS, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, and prion-like propagation. Protein aggregation counts in other neurodegenerative diseases but there is required more research to find out the same correlation in the case of ALS.
10.2.2 TDP-43 It is a DNA/RNA binding protein of 43 kDa, consists of 414 amino acids, encoded by TARDBP gene, and belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family. It is present in the nucleus containing signals for import and export from the nuclear, shuttle between cytoplasm and nucleus. It is conserved and expressed constitutively in many tissues such as the brain. It regulates gene expression and involves various RNA processing steps to pre-mRNA splicing, mRNA stability regulation, mRNA transport, translation, and noncoding RNA regulation (Giordana et al. 2010). The unusual presence of TDP-43 in the cytoplasm of affected neurons with or without mutation initiates pathogenesis with the deprivation of nuclear TDP-43 normal function, and affects transcription regulation, mRNA stability, and splicing. The absence of normal functioning of TDP-43 in the cell may
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accelerate nuclear destruction and apoptosis. TDP-43 protein dysfunction causes improper and toxic function of TDP43, this finally leads to neurodegeneration. Overexpression of both wild-type and mutant TDP-43 in rodent models can show neurodegenerative phenotype (Wils et al. 2010). The correct regulation of TDP-43 is important as a consequence of its loss and overexpression can trigger disease. There is mounting evidence suggesting that ALS may arise from abnormal TDP-43 regulation. The feedback mechanism works to regulate the TDP-43 expression as a result the protein binds on its own pre-mRNA’s 3′UTR region, promoting alternative splicing and polyadenylation that lead to the degradation, rather than translation, of mRNA transcripts when the protein is in excess in the nucleus. Nuclear TDP-43 depletion is believed to trigger continuous TDP-43 synthesis upregulation. Hence, TDP-43 homeostasis is necessary to maintain normal function of the cell, the rise in the production of TDP-43 may linked to the inclusion body formation that impairs cellular function while nuclear decrease can accelerate extensive dysregulation of mRNA metabolism. TDP-43 knockdown has shown to alter the splicing or expression of hundreds of targets (Koyama et al. 2016).
10.2.3 FUS Fused in sarcoma (FUS) is an RNA-binding protein that is another genetically associated factor of ALS. Mutations in FUS are associated with the early-onset forms of ALS and rare forms of FTD. The unusual aggregation of FUS protein has been seen in FUS-ALS that is typically found in patients with pathogenic FUS variants. FUS is RNA-binding ubiquitously expressed protein composite of 526 amino acids connected to the FET family. FUS is present primarily in the nucleus, but it can move between the cytoplasm and nucleus for nucleocytoplasmic transportation roles. FUS is also associated with various functions of gene expression like TDP-43 such as pre-mRNA splicing, RNA transport, transcription, and translation regulation. However, TDP-43 and FUS exhibit differences in their RNA targets and binding specificity. Moreover, FUS contributes to DNA repair mechanisms to join the end of homologous and nonhomologous recombination during DNA double-strand break repair. FUS is also involved in synthesis of paraspeckles to serve as a cellular defense against different types of stress (Zou et al. 2013; Gromicho et al. 2017). More than 50 autosomal dominants of FUS variants have been discovered in ALS patients. Some cases rarely reported insertion, splicing, deletion, and nonsense mutation but highly present missense mutation (Hennig et al. 2015).
10.2.4 C9ORF72 Gene The C9ORF72 gene consists of 5–10 copies of hexanucleotide (GGGGCC) repeat in normal humans. The non-coding (100–1000 of repetitions) of hexanucleotide in the C9ORF72 gene is the most common cause of ALS. The repeat expansion of hexanucleotide has been observed in approx. 34% of familial ALS cases and 5% of
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sporadic cases in the European population, low prevalence in the Asian population. However, the actual function of C9ORF72 protein is needed to investigate to understand it completely. The current research suggests its role in endosomal trafficking and autophagy regulation. Moreover, C9ORF72-deficient mouse models have shown immune dysregulation, which indicates its role in the immune system (Atanasio et al. 2016; Burberry et al. 2016).
10.2.5 CHCHD10 CHCHD10 encodes proteins in bulk at mitochondrial cristae junctions of intermembrane space. Mutations in CHCHD10 may be responsible for mitochondrial dysfunction and lead to improper morphology of mitochondrial cristae, affect mitochondrial DNA stability, and trigger mitochondrial fragmentation. First, a large French family has shown complex phenotypes, including ataxia, ALS, mitochondrial myopathy, parkinsonism, and sensorineural hearing loss, due to presence of CHCHD10 mutation. The researchers have used exome sequencing to identify mutation a p.S59L in sequence of CHCHD10. So far, extra 20 missense mutations have been reported in exon 2, which encodes an internal hydrophobic helical segment that is necessary for membrane binding in mitochondria. These types of variants have been found in all neurodegenerative disorders such as ALS, frontotemporal dementia, frontotemporal lobar degeneration, autosomal dominant mitochondrial myopathy, spinal muscular atrophy, Alzheimer’s disease, and parkinsonism. However, mutations in CHCHD10 are a rare cause of ALS but it is more common in patients with frontotemporal dementia (Dols-Icardo et al. 2015).
10.3 Minimum Association of Genes in ALS The study of next-generation sequencing of family and large groups of ALS patients has discovered the genetic variants linked with many other ALS genes. These genetic variants affect RNA processing, protein homeostasis, and cytoskeletal dynamics, but there is a lack of any evidence of the pathogenic mechanisms related to ALS. The establishment of any link between specific gene variants with disease is not fully clear yet due to a number of factors like sample size limitation in study, a smaller number of patients holding few of the variants, thus creating uncertain results. Studies have reported that DNA variants in the paraoxonase locus are associated with ALS (Saeed et al. 2006; Landers et al. 2008; Valdmanis et al. 2008). However, these findings have not been replicated when a larger genome-wide meta- analysis has been undertaken (Wills et al. 2009). Moreover, many gene variants can be a causing factor of ALS and variants also alter the ALS phenotypes or vulnerability (Diekstra et al. 2012). In contrast, deletion of copy number variation of the EPHA3 gene has been flagged as a potential protective factor for ALS (Uyan et al. 2013). Other potential risks associated with genetic modifiers of ALS have been identified such as gene variations implicated in detoxification pathways,
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highlighting the potential interplay of environment and genetic factors (Dardiotis et al. 2018). The gene variants and gene expression alter the phenotype along with susceptibility of ALS disease The disease onset and survival inversely correlated with EPHA4 expression in ALS (Van Hoecke et al. 2012).
10.4 Pathophysiology of Disease The major pathological pathways, responsible for disease progression in ALS (Fig. 10.1) are OS, axonal transport defect, neuroinflammation, excitotoxicity, mitochondrial disruption, dysfunction of oligodendrocytes, dysregulation of RNA metabolism, protein synthesis impaired, disturbance in DNA repair mechanism, improper vesicular and nucleocytoplasmic transport. Further details are mentioned below on these pathological pathways.
10.4.1 Neuroinflammation and Oxidative Stress The presence of reactive astrocytes, microglia, and elevated levels of inflammatory mediators in motor regions of the central nervous system (CNS) characterizes neuroinflammation in both form sporadic and familial ALS (Liu and Wang 2017). Microglia is an essential immune defense in the CNS, and continuously recruits
Fig. 10.1 Schematic representation of multiple pathological factors of disease ALS
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astrocytes and oligodendrocytes if they are unable to eliminate a toxic insult that results in the progression of the inflammatory process. ALS patients show abnormal proliferation of astrocytes and the same has been detected in animal models. These reactive astrocytes are expressed as inflammatory markers and inhibitory molecules to stop the growth of destructive axons. ALS patient’s spinal cordderived astrocytes show cytotoxicity in the culture of MNs. Immune cell infiltration in ALS has far-reaching consequences along the entire peripheral motor pathway, including mast cells and neutrophils accumulating around motor axons (Trias et al. 2018). Aberrant glial cells exhibit cellular stress by exacerbated endoplasmic reticulum stress, an abundance of autophagic, secretory vesicles, and reactive microglia. The activated microglia may accelerate neurotoxic effects on MNs by releasing some factors such as mitogenic factors, cytokines, neurotrophic, and anti-inflammatory factors. Cytokines (IL1α, TNFα, and C1q) released by activated microglia can trigger A1 subtypes of reactive astrocytes, which are crucial factors in neuronal death particularly neurodegenerative diseases like ALS. Cytokines levels increase in cerebrospinal fluid (CSF) in ALS, e.g., G-CSF, IL2, IL15, IL17, MCP-1, MIP1α, TNFα, and VEGF (Chen et al. 2018). A recent study suggests neuroinflammation is correlated to symptomatic phases of ALS/ FTD, the same pattern also found in sporadic and genetic cases. Overall, these findings indicate neuroinflammatory processes are a key factor in the pathogenesis of ALS (Oeckl et al. 2019). Neurodegenerative diseases are mostly associated with OS and neuroinflammation. The glial and immune cells synthesize reactive oxygen and nitrogen species more often in the CNS in pathological conditions. While ROS are not supposed to be the cause of ALS disease, in fact it is considered as an aggravating factor of the disease like these radicals can cause degeneration of neuromuscular junction in ALS. The level of antioxidant like glutathione (GSH) also gets decrease in the motor cortex in ALS patient as compared to normal human (Graves et al. 2004; Bettelli et al. 2006; Chiu et al. 2008; Zhao et al. 2012; Henkel et al. 2013). Additionally, MNs get overstimulated by amino acid-mediated excitation that can release the unusual enzyme acetylcholinesterase, leading to reduce in acetylcholine levels in the synaptic cleft as a result of loss of muscle strength occur in ALS patients. The pathogenesis of neurodegenerative diseases involves a complex interplay between neuroinflammation and OS (Liu and Wang 2017). Another factor involved in disease pathogenesis of ALS is Nrf2, master regulator of cryoprotection mechanism, and detoxification. Mutant TDP-43 protein is associated with ALS since it stimulates OS and destruction of mitochondria that induce accumulation of Nrf2 in nuclear. Protein and mRNA levels of Nrf2 are reduced in astrocytes and Nrf2 signaling is vital for reducing neuroinflammation in ALS by inhibiting the adverse effect of microglia on neurons (Neymotin et al. 2011; Pollari et al. 2014). Overall, OS and neuroinflammation work together in the pathogenesis mechanism of ALS. Targeting the Nrf2 antioxidant response element may provide a promising therapeutic approach for ALS by attenuating neuroinflammation and enhancing antioxidant defenses (Neymotin et al. 2011).
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10.4.2 Excitotoxicity It is a key mechanism of pathophysiology in ALS and excessive stimulation of postsynaptic glutamate receptors causes neurotoxic effects through increased intracellular calcium levels. Prolonged excitotoxicity leads to pathological changes, including endoplasmic reticulum stress and mitochondrial calcium overload (Kazama et al. 2020). Excessive glutamate exposure inhibits the glutamate-cystine antiporter as a result decrease in cysteine uptake, depletes intracellular antioxidant glutathione levels, and increases OS in the cell. MNs have unique features that make them more vulnerable to increase their susceptibility to excitotoxic damage such as calcium-permeable AMPA receptors’ expression increase with deficient GluR2 subunit and expression of the calcium-buffering proteins like parvalbumin and calbindin reduction. C9orf72 mutations impair mitochondrial calcium-buffering capacity and increase Ca2+ permeable AMPA receptor-mediated excitotoxicity in induced pluripotent stem cell-derived MNs (Van Damme et al. 2005; Selvaraj et al. 2018). Therefore, excitotoxicity is a critical mechanism in the pathogenesis of ALS that involves a range of cellular and molecular changes in MNs, including altered expression of calcium channels and transporters, leading to excessive calcium influx and mitochondrial dysfunction (Lewerenz et al. 2013). Though, the drug riluzole is commonly used in the treatment of ALS still it is very complex to understand its mechanism of action, one component of this drug action is thought to reduce glutamate release from presynaptic terminals via an effect on presynaptic sodium channels that may help to alleviate excitotoxic effects on MNs (Lamanauskas and Nistri 2008). Current drug development programs are trying to reformulate the drug riluzole to synthesize various forms of drug such as stable liquid and sublingual preparation to target the excitotoxicity of glutamate. Additionally, metabotropic glutamate receptors are emerging as novel potential drug targets in ALS, as their modulation may lead to a decrease in glutamate release and induction of neurotrophic factors production (Battaglia and Bruno 2018).
10.4.3 Protein Homeostasis The correct protein synthesis and deprivation maintained by complicated networks including protein generation, trafficking, and degradation pathways, this process is accelerated by stress signals such as mitochondrial stress, ER stress, heat shock, and unfolded protein responses. Age-related neurodegenerative disorders show proteome stress, accumulation of non-native proteins, and oxidatively damaged proteins. This indicates a loss of proteostasis in aging cells (Webster et al. 2017). ALS-causing gene-encoded proteins generally maintain a proteostasis network, so proteostasis dysfunction has a profound role in disease progression either directly or indirectly. In addition, proteins related to ALS serve as substrates for the proteostasis pathways, including SOD1 and TDP-43. Autophagy is initiated by C9ORF72, sequestosome 1/P62, optineurin, and ubiquitin 2, proteins (e.g., ubiquilin2, alsin, FIG4, VCP, and CHMP2B) and control autophagosome maturation (Oakes et al.
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2017; Webster et al. 2016). MNs may be more susceptible to proteome stress due to their size, axonal arbor, lower expression of ubiquitin-proteasome genes, and relative inability to mount an effective heat shock response (Brockington et al. 2013).
10.4.3.1 Nucleocytoplasmic Transport Defects The mis-localization of FUS and TDP-43, RNA-binding proteins from normal position of nucleus to cytoplasm occur in ALS cases and defects in nuclear transport may also impact the mechanism of disease. C9ORF72 hexanucleotide repeat expansion has shown evidence of defect in nucleocytoplasmic transport. Modifiers of C9ORF72 toxicity uncovered about 18 genetic modifiers related to nucleocytoplasmic transport and RNA export in genetic screening. This highlights the significance of this system as a primary target of hexanucleotide repeat expansion-related toxicity (Freibaum et al. 2015).
10.4.4 Impaired DNA Repair The ALS-linked proteins, TDP-43 and FUS play a role in preventing or repairing transcription-associated DNA damage. FUS participates in repairing of doublestranded DNA breaks through both homologous recombination and nonhomologous end-joining repair mechanisms (Wang et al. 2013). Other ALS-linked RNA-binding proteins also associated with impaired DNA damage repair, including TAF15, SETX, and EWSR1, further connect the breakdown of this process in ALS pathogenesis.
10.4.5 Vesicular Transport Defects Proteins related to defective vesicular transport involved in ALS such as OPTN, VAPB, CHMP2B, and UNC13A (Cox et al. 2010; Vidal-Taboada et al. 2015; Chadi et al. 2017; Sundaramoorthy et al. 2017). Vesicular trafficking inhibition from the Golgi to the plasma membrane for a prolonged period can lead to protein accumulation and fragmentation of the Golgi (Zhou et al. 2013; Sundaramoorthy et al. 2017). Fragmentation of the Golgi is a prominent histopathological feature observed in ALS patients (Fujita and Okamoto 2005; Fujita et al. 2007), and studies suggest that it can be an early trigger of neurodegeneration rather than a consequence (Gonatas et al. 2006; Dis et al. 2014).
10.4.6 Axonal Transport Impaired The movement and allocation of molecules, such as proteins, lipids, organelles, membrane-bound vesicles, and mRNA, are maintained by axonal transport in the axon. Cellular structure and function are maintained by axonal transport and enable long communication between synaptic terminals and the cell body. Neurodegenerative
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diseases frequently exhibit defects in axonal transport (Millecamps and Julien 2013). Postmortem studies provided early evidence for axonal transport defects in ALS like demonstrating abnormal accumulations of neurofilaments, mitochondria, lysosomes, spheroids containing vesicles, and microtubules (Rouleau et al. 1996; Sasaki and Iwata 1996). Subsequently, axonal transport impairment was detected in SOD1 animal models (Ligon et al. 2005; Bilsland et al. 2010). Pathogenic variants in axonal transport machinery and cytoskeletal genes have been identified as a primary cause of ALS (Smith et al. 2014). TDP-43 is believed to contribute to axonal transport defects in ALS by assisting in the delivery of mRNA via active axonal transport (Akira et al. 2016). Axonal transport defects are detected early in disease progression prior to symptom onset, and this specifies a potential role in the pathogenesis of ALS (Williamson and Cleveland 1999).
10.4.7 Oligodendrocyte Dysfunction Oligodendrocytes are responsible for producing the myelin sheath to insulate the axons of nerves and neurons in the CNS (Bradl and Lassmann 2010). The potential participation of nonneuronal cells, particularly oligodendrocytes, are found in the pathogenesis of ALS. While gray matter oligodendrocytes do not participate in myelin sheath formation, in fact considered to provide metabolic support to neurons (Nave 2010; Philips and Rothstein 2017). The changes in lactate production by oligodendrocytes could contribute to axonal degeneration. Lactate transporter MCT1 is highly expressed in oligodendrocytes, but its level is reduced in the motor cortex of ALS patients and animal models of the disease (Lee and Kim 2015). In addition, impaired function and extensive degeneration of gray matter oligodendrocytes occur in the spinal cord along with oligodendrocyte precursors failing to fully differentiate (Kang et al. 2013). However, it is still uncertain whether these changes in oligodendrocytes precede a neuronal loss or consequence of it. Moreover, alterations in myelin structure in the spinal cords may also count as contributing factors of ALS at presymptomatic stages and early in disease progression (Niebroj-Dobosz et al. 2007; Kang et al. 2013).
10.5 Various Strategies to Improve ALS Clinical trials have shown extreme failure rates in ALS due to several reasons, such as the complexity of the disease, small patient populations, lack of reliable biomarkers, and heterogeneity of patient populations. However, there are many mitigation strategies that could lead to a substantial improvement in effective therapy development. First, validating biomarkers identified in ALS can help to improve patient selection and stratification, leading to targeted effective therapies, and this can be achieved by using advanced imaging techniques, genomics, and proteomics, as well as through the analysis of patient-derived samples such as CSF and blood (Vucic et al. 2021). Second, the use of platform trials can help to reduce the cost and time
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required for drug development in which multiple therapies are evaluated simultaneously. This approach allows for the evaluation of multiple treatments against a common control arm, enabling more efficient patient recruitment and data collection. Third, the implementation of adaptive trial designs can enhance trial efficiency by reducing failure. This method is suitable for modifications to make the trial protocol based on interim data analysis, such as changes to patient inclusion criteria, dosing, or sample size, this will increase the success. Finally, more patient engagement and participation in clinical trials can expand patient recruitment, retention, and improve adherence, which will lead to more representative and reliable trial data. This can be achieved using patient-centered trial designs, community outreach, and patient advocacy. The success rates of clinical trials in ALS will improve by implementing these mitigation strategies and lead to more effective therapies with better outcomes for patients.
10.6 Biomarkers Recent advancement has been made in detecting biochemical biomarkers, particularly in gene therapy trials for ALS. For example, tofersen is an antisense oligonucleotide therapy that aims to decrease the levels of SOD1 protein. It shows dose-dependent reductions in SOD1 protein levels in the CSF in SOD1-correlated ALS. Neurofilament light (NFL) levels in blood and CSF have also emerged as potential biomarkers of motor neuron injury and therapeutic efficacy (Iannitti et al. 2018). The NFL shows value in diagnosing ALS as well as predicting disease progression and monitoring pharmacodynamic responses. Additionally, transcriptomics analysis of peripheral blood mononuclear cells has shown promise in detecting gene expression biomarkers for good and poor responses to experimental compounds, as well as predicting the level of response (Miller et al. 2020). Despite these promising developments, a phase I trial of a C9orf72-ASO showed robust dose-dependent lowering of dipeptide repeat proteins without evidence of clinical benefit. Hence, further research is necessary to identify reliable biomarkers and to develop therapy in ALS (Miller et al. 2020). While microRNAs have potential as biomarkers for ALS but lack consistency in the result to identify microRNAs due to uncertain expression among various laboratories. However, a study mentioned that elevated levels of miR-181 in plasma predict an increased risk of death in both an independent discovery patient cohort and a replication patient cohort (Magen et al. 2021). The combined test of miR-181 with NFL may increase the accuracy of analysis in ALS. The neurophysiological index has been proposed as a quantitative measure of peripheral disease burden in ALS (Pinto and de Carvalho 2010). Imaging studies can be promising imaging biomarkers for further trials, including PET ligands and magnetic resonance spectroscopy (MRS). Probing the biology of the CNS can be achieved by using proton MRS, which measures metabolites including N-acetyl aspartate (NAA), a neuronal marker, myoinositol, a glial marker, choline- containing compounds, amino acids, and neurotransmitters such as glutamate and GABA. MRS also measures bioenergetic status, such as derivatives of ATP, and
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glutathione, as a measure of oxidative status (Verber et al. 2019). Another potential method for monitoring disease is positron emission tomography (PET), either alone or with magnetic resonance imaging (PET-MRI). FDG PET analyses glucose uptake in cells and is beneficial in finding cerebral metabolic activity in ALS patients (Pagani et al. 2014).
10.6.1 Diagnostic Biomarkers The diagnosis is challenging to exclude other diseases, present similarly can take over a year in ALS. Moreover, the varied presentation of ALS further complicates diagnosis (Pagani et al. 2014). A specific and sensitive biomarker for ALS would aid in decreasing uncertainty and time to diagnosis, ultimately earlier interventions can be initiated, and this will increase the time window for clinical trial eligibility. However, the identification of a biomarker can make it easier to distinguish between ALS versus control as well as other ALS-mimicking diseases, otherwise its difficult and leads to therapeutic trials primarily based on clinical scales and requiring longer observation to assess (Al-Chalabi et al. 2016).
10.6.2 Prognostic Biomarkers Clinical trials rely on the ALS Functional Rating Scale-Revised (ALSFRS-R) or analogous scale to measure the effectiveness of potential treatments in ALS. These scales measure the deterioration, maintenance, or recovery of function in regular activities by analysis of biomarkers. However, the biomarkers in blood can be beneficial prognostic biomarkers if it relate to progressive inflammation and a decrease in ALSFRS-R during disease. Such biomarkers could predict the rate of decline in disease progression in a patient, and potentially distinguish between disease subgroups, such as slow and rapid progressors (Sun et al. 2020). The development of specific and sensitive biomarkers could also be helpful in identifying patients with slower or faster disease progression and more targeted clinical trials can be designed for personalized treatments. In turn, this could reduce the cost and time required for drug development and increase the probability of successful outcomes for patients with ALS (Mohanty et al. 2020).
10.6.3 Pharmacodynamic Biomarkers It plays a crucial role in confirming whether a therapeutic strategy has exerted the expected effect on a participant during the treatment paradigm (Philips and Robberecht 2011). Pharmacodynamic biomarkers can confirm target engagement and assist in detailing target validity. The pharmacodynamic biomarkers have aided the understanding of drugs or targets in ALS (van den Berg et al. 2019; Kiernan et al. 2021). Overall, the inclusion of pharmacodynamic biomarkers can support in
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proving target engagement and informing target validity, potentially uplifting more efficient drug development in ALS.
10.7 Conclusion Researchers in the field of ALS face a number of challenges to understand the details of disease and effective treatment development. Many questions regarding underlying genetic factors remain unanswered in case of ALS. To fill these knowledge gaps, there is a need to shift focus toward investigation of genetic modifiers of disease, such as structural variants, repetition variations, and intron DNA regions, during diagnosis. TDP-43 participates in most ALS cases but the stage at which it becomes implicated in disease progression and post-translational modifications of TDP-43, is essential to know further details on it. The function of protein aggregation in ALS toxicity also needs a more detailed explanation. The extensive genetic variation associated with ALS and the impact on multiple cellular pathways suggests a significant level of heterogeneity among patients. Animal models have limitations in replicating the full range of human ALS phenotypes, which makes it challenging to unravel the causes and identify effective treatments. Personalized medicine is gaining attraction in various medical fields, including cancer treatment. Thus, implementing personalized medicine in ALS could be beneficial in identifying subtypes of patients that show different responses to potential therapies. Establishing clinical biomarkers for ALS subtypes would be highly recommended if based on genetic and nongenetic information. Complete genetic information may aid effective treatments for specific subgroups of patients. A comprehensive biological knowledge could enhance our understanding of ALS to improve diagnosis through biomarkers, to synthesize personalized and effective treatment strategies.
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Modulators and Poststroke Behavioral Changes
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Rahul Saxena, Babita, Suyash Saxena, and Sudipta Kundu
Abstract
Neuro-pathophysiological conditions like cerebrovascular accident (CVA) or stroke are linked to insufficient blood flow to the brain, which causes cell necrosis, a dynamic and complex event. Stroke ranks third in terms of disabilityadjusted life years and this condition is the second major cause of mortality. The cerebral vasculature, an important target of oxi-inflammatory stress-driven biomolecular degradation, is interestingly playing a significant role in the etiology of ischemic brain injury following a cerebrovascular event. Peripheral lymphocytes that enter ischemic areas of the brain coordinate inflammatory reactions, complement cascade, trigger tissue death, and worsen stroke clinical outcomes. Therefore, developing combination therapies that focus on multiple mechanisms or cellular pathways may be more successful than using single therapies alone. Moreover, stroke survivors frequently experience emotional and behavioral changes, which includes irritability, cognitive impairment, disability, inattention, disorientation, and feelings of anger, anxiety, or depression. Despite a plethora of neuroscientific initiatives and therapeutic efforts, several remedial pages are still unfinished and require more significant clinical insight not only to resolve the conundrum of CVA but also to mitigate the burden of stroke. This chapter reviews various types of stroke modulators such as ion channels, transcription factors, receptors, gene modulators, and their metabolic rate. This review also highlights R. Saxena (*) · S. Saxena Department of Biochemistry, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India Babita Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India S. Kundu Department of Human Physiology, Kalka Dental College, Meerut, Uttar Pradesh, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_11
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pathophysiologic damage with particular emphasis on poststroke behavioral changes in survivors. Keywords
Oxi-inflammatory stress · Complement cascade · Ionic imbalance · Anxiety · Depression
Abbreviations CDC Centers for Disease Control and Prevention CNS Central nervous system CVA Cerebrovascular accident CVDs Cardiovascular diseases DM Diabetes mellitus miRNAs MicroRNAs S1PR Sphingosine-1-phosphate receptor SCD Sickle cell disease TIA Transient ischemic stroke TMS Transcranial magnetic stimulation WSO World Stroke Organization’s
11.1 Introduction “The forms of diseases are many and the healing of them is manifold”—Hippocrates commented these words centuries ago and received much attention worldwide (Jones 1931). In this context, Hippocrates in his writings (c. 400–200 BC) introduced the term “apoplexy.” He defined apoplexy as a disease condition, characterized by a sudden loss of consciousness, motion, and sensation. Today, the medical term “apoplexy” is no longer widely used and has generally been supplanted in clinical settings by “stroke.” Early in the twentieth century, the term “cerebrovascular accident,” often known as a “CVA,” was introduced. During that time, vascular theories were becoming more well-known and accepted, and physicians began to understand the effects of a sudden disruption in the brain’s arterial supply. In modern understanding, stroke is a medical emergency, also known as a transient ischemic attack or a CVA. It occurs when the brain’s blood supply is restricted, depriving it of oxygen and nutrients in the blood (Auer and Sutherland 2002). As a result, minutes after the injury, brain cells start to die, which is followed by permanent impairment or even death. Interestingly, despite the fact that numerous therapeutic interventions and neuroscientific endeavors have been made in order to comprehend the molecular basis of cellular function and to alleviate the burden of stroke, many remedial pages remain unwritten and require more thorough clinical
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understanding to resolve the mystery of CVA. According to the World Stroke Organization’s (WSO) Global Stroke Fact Sheet 2022, between 1999 and 2019, there was a projected 70% increase in the incidence of stroke and a 43% increase in the number of stroke deaths among residents of low- and lower-middle-income countries (Feigin et al. 2022). According to the Centers for Disease Control and Prevention (CDC), more than 795,000 Americans experience a stroke each year, making it the leading cause of death in the country (Capriotti and Murphy 2016). Moreover, stroke is the second most common cause of death in India. In India, about 185,000 stroke cases have been documented every year with nearly one stroke every 40 s and one stroke death every 4 min. However, the incident of stroke is not completely mendable, and it is acknowledged that the culprit is an influx of CVA followed by a cloud of stroke-related complications and mortality.
11.2 Types of Strokes There are three types of strokes:
11.2.1 Ischemic Stroke This is the most common type of stroke which occurs due to the blockage of arteries in the brain due to some clot or plaque. Since the supply of blood to a certain part of the brain is hampered, this can lead to lasting damage to the brain. Based on etiology, there can be three subtypes of ischemic stroke: arteriosclerotic ischemic stroke, thrombotic ischemic stroke, and embolic ischemic stroke. In 1991 Bamford et al. from Oxford University classified ischemic stroke based on the site and size of the lesion of stroke, which is now popularly known as the Oxford Community Stroke Project classification (Bamford et al. 1991). This classification is based on the CT scan findings of cerebral infarction. According to this classification, there can be four identifiable subgroups of ischemic strokes: total anterior circulation infarcts, partial anterior circulation infarcts, lacunar infarcts, and posterior circulation infarcts.
11.2.2 Transient Ischemic Stroke (TIA) TIA, happens when the blood supply to the brain is momentarily cut off. It also goes by the name “Mini stroke.” It serves more as a warning indication for ischemic stroke in the future. In this situation the clot resolves within a few minutes. Although there are no long-term effects from TIA, there is a minimal distinction between the symptoms of TIA and the actual stroke at the time of the stroke.
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11.2.3 Hemorrhagic Stroke When an artery leaks or it gets ruptured due to some reason, the blood oozes out and accumulates in the brain area and causes pressure on the brain tissues around, this leads to damage to the brain. This is called as hemorrhagic stroke. It can be of two types: intracerebral hemorrhagic stroke and subarachnoid hemorrhagic stroke.
11.3 Risk Factors of Stroke With a few major exceptions, the contributing factors for ischemic and hemorrhagic stroke are virtually the same. Some of risk variables can be managed or changed whereas few factors, such as genetics, age, ethnicity, and sex, cannot be managed or changed. The comorbid conditions like high blood pressure, diabetes mellitus (DM), alcohol use, smoking, infection, stress, obesity, inactivity, hyperlipidemia, and diet are among the modifiable risk factors. The common risk factors for ischemic stroke include inactivity, DM, cardiovascular diseases (CVDs), depression, emotional and behavioral stress, and higher levels of apolipoprotein B. It is noticeable that these variables are involved in the majority of stroke incidences. In addition, sickle cell disease (SCD) is also considered as a risk factor for stroke (Hankey 2017).
11.4 Symptoms of Stroke In most of the stroke cases, the symptoms develop quickly but sometimes it may take hours or even days to develop. The symptoms depend on the type of stroke, area of the brain, and the degree of damage caused to the brain. It includes feeling of sudden weakness or complete loss of control on one side of the body, state of confusion, slurring of speech or difficulty in speaking clearly, blurring, or complete loss of vision in one or both eyes, loss of balance and coordination of the body, difficulty in walking straight, sudden severe headache of unknown reason, and or face drooping on one side.
11.5 Modulators of Stroke There are various sorts of modulators (Table 11.1) which include:
11.5.1 Neuro Modulators Neuromodulation is a well-documented disruption of the excitatory-inhibitory balance in neural networks after an ischemic stroke.
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Table 11.1 Types of modulators of stroke Category (a) Neuromodulators
(b) Pharmacological modulators
Modulators of stroke 1. Modulation by cortical stimulation 2. Modulation by cerebellar stimulation 3. Modulation by vegal stimulation 4. Modulation by optogenetics 1. Sphingosine-1-phosphate receptor 2. microRNAs (miRNAs) mediated polarization of microglia 3. microRNA-124 and microRNA-145 modulation 4. d-Amphetamine 5. Levodopa 6. Sigma 1-receptor agonists 7. Fluoxetine 8. Niacin 9. Inosine 10. Nogo-A inhibition 11. Reduced tonic inhibition 12. Phosphodiesterase 5 inhibitors
11.5.1.1 Modulation by Cortical Stimulation It is a crucial tactic to improve poststroke healing by rearranging neuronal circuitry and restoring the excitatory-inhibitory balance of the injured brain. Implantable epidural electrodes, transcranial magnetic stimulation (TMS), and other invasive and noninvasive techniques have all been investigated (Woods et al. 2016). 11.5.1.2 Modulation by Cerebellar Stimulation The cerebellum has also been treated using TMS. Recently, Bonn et al. used TMS on patients with ataxia brought on by persistent posterior circulation ischemic stroke in the lateral cerebellum. The authors saw advancements in clinical and neurophysiological conditions. In preclinical mouse models, it has been demonstrated that deep brain stimulation of the cerebellothalamic-cortical system, particularly of the lateral cerebellar nucleus, can modify cerebral cortex excitability and enhance postischemia motor recovery (Machado et al. 2019). 11.5.1.3 Modulation by Vagal Stimulation Researchers believe that vagal nerve stimulation can increase neuroplasticity and encourage the reorganization of neural networks considering the discovery that extensive training has been demonstrated to facilitate a variety of neuroplastic brain events (Cramer et al. 2011). 11.5.1.4 Modulation by Optogenetics Activation-dependent factors that remodel neuronal connections and speed recovery can be released by neurons in living cells. A way to regain functional ability is to control these neurons’ excitability. With the use of genetically altered live cells that exhibit light-sensitive ion channels, optogenetics allow living cells, particularly neurons, to be controlled (Cheng et al. 2014).
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11.5.2 Pharmacological Modulators 11.5.2.1 Sphingosine-1-Phosphate Receptor Modulators (S1PR) S1PR modulators are hypothesized to predominantly act in these two ways to decrease lymphocyte exocytosis from lymphoid organs, which decreases the number of lymphocytes in the bloodstream of the peripheral organs and the central nervous system (CNS). S1PR modulators have direct effects on the CNS in addition to restricting lymphocytes, according to an increasing number of studies. S1PRs are expressed by astrocytes, microglia, oligodendrocytes, neurons, and blood-brain barrier vascular endothelial cells. S1PR modulators may interact with these S1PRs in order to function. In both ischemic and hemorrhagic stroke, S1PR modulators have shown immediate neuroprotective and anti-inflammatory advantages (Wang et al. 2016). 11.5.2.2 microRNAs (miRNAs)-Mediated Polarization of Microglia From a resting state, microglia typically polarize in two directions. The M1 phenotype, or classical activation, is connected to the production of cytokines, which exacerbates the damaging effects of the stroke on the brain tissue. The neuroprotective effects are due to the M2 phenotype, an alternative activation that supports brain cell healing and repair after ischemia (Qing et al. 2018). 11.5.2.3 microRNA-124 and microRNA-145 Modulation MiR-124, according to a recent study, is essential for regulating the M2 phenotype. A surface indicator of the M2 microglia/macrophage phenotype is arginine-1 (Arg-1). Hamzei Taj et al. (2016) reported that miR-124 increased the expression of Arg-1, and that this shift was linked to neuroprotection and better functional outcomes. The formation of the M2a state might be aided by the overexpression of miR-145. 11.5.2.4 d-Amphetamine Amphetamine, a strong psychomotor stimulant that encourages the release of neurotransmitters like norepinephrine and serotonin from neurons, has been shown to improve motor recovery in animal models of stroke and various other brain injuries. These functional improvements are associated with increased axonal flexibility as well as the development of novel anatomical pathways (Cheatwood et al. 2008). 11.5.2.5 Levodopa The precursor for the transformation of dopamine into norepinephrine is levodopa (l-3,4-dihydroxyphenylalanine). After an ischemic stroke, persons who are receiving delayed levodopa treatment together with physical therapy can regain their functional motor skills (Scheidtmann et al. 2001). 11.5.2.6 Sigma-1 Receptor Agonists Sigma-1 receptor expression is increased in the brain cells of rats living in a richly enriched setting after localized cerebral ischemia. In surviving cells, particularly
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astrocytes, in the peri-infarct region of animals with good brain function recovery, the expression of the sigma-1 receptor is increased, according to a more in-depth analysis of the role of the gamma-1 receptor in recovery after stroke. The membrane rafts of astrocytes and neurons contain the gamma-1 receptor, which is necessary for membrane raft trafficking and neurite development. Importantly, when given within 2 days of stroke induction, the potent and selective-1 receptor agonist SA45031 improved functional recovery in rat models of stroke (Ruscher et al. 2011).
11.5.2.7 Fluoxetine The sudden onset rises in synaptic monoamine levels brought on by antidepressants cause subsequent, long-lasting neuroplastic changes and regulates molecular and cellular plasticity through transcriptional and translational changes. Selected serotonin reuptake inhibitors enhance hippocampal neurogenesis, boost spatial cognitive deficits in rats that were caused by ischemia, and are neuroprotective in the postischemic brain because of their anti-inflammatory effects. Fluoxetine for motor recovery after acute ischemic stroke demonstrated that combining physiotherapy with early fluoxetine treatment improves motor recovery and lowers the number of dependent patients when compared to physiotherapy alone in a larger cohort of patients with moderate-to-severe hemiplegia following ischemic stroke (Chollet et al. 2011). 11.5.2.8 Niacin The medicine that is now most successful at treating dyslipidemia is niacin. A prolonged-release niacin formulation called Niaspan was administered to rats commencing 24 h after localized brain ischemia. This medication may have improved functional outcomes through a synergistic effect of its impact on angiogenesis, and arteriogenesis, along with increased synaptic remodeling, and axon growth (Cui et al. 2010). 11.5.2.9 Inosine The purine inosine is provided by nature. Ensuing unilateral stroke induction, intracerebral infusion of inosine stimulated neurons on the unaffected side of the brain to forge fresh connections with denervated regions of the midbrain and spinal cord, improving behavioral outcomes in rats. Inosine changed the oblique gene expression of the stroke-related neurons, enhancing their capacity to interact with nearby cells on the denervated side of the spinal cord (Zai et al. 2009). 11.5.2.10 Nogo-A Inhibition Neurite outgrowth is inhibited by the myelin-associated protein Nogo-A, which lowers plasticity and healing after CNS injury. Anti-Nogo-A antibody therapy after cortical lesions enhanced dendritic arborization, increased axonal plasticity from the unaffected hemisphere, and boosted the spine density of pyramidal neurons in the contralesional sensorimotor cortex. As a result, functional recovery was enhanced (Papadopoulos et al. 2006).
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11.5.2.11 Reducing Tonic Inhibition Damaged areas can be used to remap sensory processes as a result of increased neuroplasticity in the peri-infarct zone after stroke. Tonic neural inhibition, which is brought on by extrasynaptic-aminobutyric acid A receptors and is brought on by a problem with astrocytes’ capacity to take in aminobutyric acid, however, counteracts this peri-infarct neuroplasticity, which is necessary for rehabilitation (Clarkson et al. 2010). 11.5.2.12 Phosphodiesterase 5 Inhibitors Phosphodiesterase 5 is an enzyme that breaks down cyclic guanosine monophosphate, a second messenger molecule. Brain cells and smooth muscle cells in blood arteries both express phosphodiesterase 5. When it is pharmacologically inhibited, arterial dilatation occurs, which is utilized to treat erectile dysfunction. To speed up functional recovery, phosphodiesterase 5 inhibitors (sildenafil, tadalafil) were given orally to young and old experimental animals starting 24 h after the stroke. This improvement may have been brought about by increased cerebral blood flow, angiogenesis, neurogenesis, and synaptogenesis (Zhang et al. 2005, 2006).
11.6 Poststroke Physical Complications Stroke can cause a variety of complications depending on the area of the brain, severity of the stroke, and the degree of damage caused to the specific part of the brain. The complications of the stroke are generally long-lasting or in some cases permanent damage can also occur. The common complications include slurring of speech or difficulty in speaking, loss of touch and sensation of temperature, blurred vision and loss of hearing, loss of control and weakening of muscles, unusual muscle spasms, loss of coordination and balance in the body, loss of mobility, loss of bone density, difficulty in swallowing, risk of inhaling food into the lungs, leading to pneumonia, loss of control over urinary bladder and bowel activity, swelling in the brain, seizures, and venous thromboembolism.
11.7 Poststroke Cognitive Changes Cognitive changes are the changes noticed in the ability of thinking, communication, memory loss, and problem-solving ability. The effects of stroke are different for everyone but the effects can be noticed based on the side of the brain affected. The common cognitive changes after left brain stroke include aphasia, dementia, impaired ability to do mathematical calculations and reasoning, impaired ability to analyze and organize things and impaired ability to read, write, and grasp new information. The common cognitive changes after right brain stroke include left neglect, impaired ability to solve spatial perceptual tasks, inability to read, and dementia.
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11.8 Poststroke Behavioral Changes Stroke damages the brain, and the brain controls our voluntary and involuntary movements. It also controls our memories, thoughts, emotions, and behavior. Due to loss of control of own body and the disabilities that a patient goes through can lead to various behavioral changes in the patients after the stroke.
11.8.1 Personality Changes Stroke survivors go through a lot of changes in their life after stroke. These changes are not just at physical or cognitive level but sometimes it may change their entire personality ranging from apathy, neglect, or impulsiveness.
11.8.2 Low Self-Esteem Poststroke patients are dependent on their family members and caregivers for almost everything, including their small chores like sitting, using washroom walking, and eating. They may feel discouraged and can suffer from low self-esteem.
11.8.3 Pseudobulbar Affect Reflex crying, involuntary emotional expression, and emotional lability are some names for it. Pseudobulbar affect happens when there is a disconnect between the cerebellum and brain stem, which mediates reflex response, and the frontal cortex, which regulates emotions. The abrupt, uncontrollable laughing or crying that may linger longer than normal is what distinguishes this.
11.8.4 Attention Deficit Stroke patients frequently experience attention deficits, which have a significant impact on their quality of life and success in rehabilitation.
11.8.5 Inappropriate Behavior In cases of stroke patients with damage in the frontal lobe, patients lose the ability to read the social situations or the basic communication tact such as to maintain personal distances with the people, interrupt others while they are talking, giving tactless inappropriate remarks on the others without thinking thorough or spending impulsively. In some cases, it is also noticed that the patient becomes self-centered and stubborn and refuses to do anything which he does not want to do.
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11.8.6 Changes in the Libido After the stroke the sexual urges can also be changed. The patients can show increased or decreased libido. The decrease in the libido is very common post- stroke in the patients. This change is usually due to the problems related to the recovery and the self-doubt about one’s own physical abilities and one of the major reasons for decreased libido could be the antidepressants as a part of treatment (Calabrò et al. 2011). In few cases, stroke survivors also report increased sexual urges in their behavior.
11.8.7 Depression Although depression is not as such a behavioral trait it has a direct and indirect effect on the overall personality and behavior of the patients. Almost one-third of stroke survivors go through depression and the situation improves with time in most of the cases as the patient recovers from the damages of stroke and gains his physical abilities again or he adapts the lifestyle to the difficulties caused by the stroke.
11.9 Conclusion Stroke is a multifactorial pathophysiological incident that deteriorates the brain in a complex and dynamic manner. Despite its prevalence worldwide, still there is a lack of effective therapeutic interventions. Consequently, this highlights the need for more focused and coordinated efforts worldwide to better understand the underlying mechanisms of stroke and ultimately reduce its incidence. Intriguingly, based on the literature mentioned in the present review, it is crucial to highlight the risk factors of stroke at the community level, which would result in the creation of stronger awareness and preventative measures against stroke-mediated mortality and disability as well. Furthermore, considering the modulators and current data relating to poststroke physical, behavioral, and cognitive changes, the future research should be aimed at more than one mechanism/cellular pathway to develop multifaceted treatments along with rehabilitation strategies to meet the needs of stroke survivors.
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Presynaptic Dysfunction in Parkinson’s Disease
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Koyel Kar
Abstract
Parkinson’s disease (PD) is followed by neurodegeneration that causes impairment of body movement, nervous system abnormalities, and sleep disorders. These signs are brought on by dopamine neuronal deprivation in the substantia nigra of the brain. The drugs available will lessen the symptoms but the advancement of the disease cannot be ceased. Different studies manifested that synaptic dysfunction and degradation of axons take place earlier than the loss of neurons. The detection of synaptic changes in the early stage may prove to be helpful in the prevention and slow advancement of the disease. Imaging studies executed with specific ligands and dissection studies in animal models exemplify dysfunction in the presynaptic terminals. The dopaminergic synapses get diminished in PD, but the role of other neurons causing the degradation of synapse remains obscured. Different genes present at the synapse are also responsible for causing the dysfunction of synapses. This chapter describes the following agendas: (1) first, the defects in synapses occur much before the death of the neuron; (2) second, it exhibits the specific genes contributing to the dysfunction of the synapse; and (3) third, the interrelation between the neurons in the striatum and that of the synaptic genes in different neurons have been established. Thus, this study will facilitate the creation of innovative therapies by targeting the synapse. Further studies and research are required to inspect the roles of these genes in different neurons. Keywords
Presynaptic dysfunction · Lewy bodies · α-Synuclein · PD · Risk genes · Mutation K. Kar (*) Department of Pharmaceutical Chemistry, BCDA College of Pharmacy & Technology, Hridaypur, North 24 Parganas, India, West Bengal © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_12
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Abbreviations AP Atypical parkinsonism BAC Bacterial artificial chromosome DAT Dopamine transporter DJ-1 Protein deglycase also known as Parkinson’s disease protein 7 EPSC Evoked excitatory postsynaptic current GABA Gamma-aminobutyric acid HSC70 Chaperone-mediated autophagy carrier LB Lewy bodies LTP Long-term potentiation NMDA N-methyl-d-aspartate NSF N-Ethylmaleimide sensitive factor PINK1 Pten induced kinase 1 ROS Reactive oxygen species SNARE Soluble N-ethylmaleimide-sensitive factor attachment protein receptor SV Synaptic vesicle SV2A Synaptic vesicle glycoprotein 2A
12.1 Introduction Parkinson’s disease (PD) can be described as a disease accompanied by neurodegeneration. It is commonly seen in geriatric persons. Motor-related activity is disturbed causing rigidity of muscles, bradykinesia, akinesia, gait abnormalities, and tremor in the body. Other associated features are hyposmia, dysfunction of the autonomic system, and sleep disorder. In PD, dopamine neurons are degraded in the substantia nigra of the brain. Neurons of dopamine consist of very weak axons in the striatum, which controls the secretion of dopamine and also regulates the characteristics of neuronal projections (Calabresi et al. 2014). This activity inhibits the thalamus and cortex, leading to the rigidity of muscles and bradykinesia (Wichmann 2019). The dopamine loss not only occurs in the substantia nigra but also in various regions of the brain. The neurons and different nuclei such as the pedunculopontine, supraoptic, and amygdala are fully degraded because of cellular loss (Surmeier et al. 2017). Recently, a review was carried out to determine the loss of cells in PD based on the number of neurons. The neuronal deprivation can be well-determined stereologically as this process involves meticulous sampling. Neuronal deprivation in the cholinergic system also occurs, which can also be determined stereologically. The cholinergic neurons are also lost in the brain’s dorsal part. The neuronal deprivation in the noradrenergic system is also analyzed by stereology (Harding et al. 2002). Thus, it can be concluded that loss of cells occurs throughout the brain but the degradation of neurons in all parts of the brain will require further affirmation. Sometimes, it is seen that the cells are not dying completely in PD. So, the role of neurons and other factors causing PD is still very vague. In the later phases of PD,
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the α-synuclein protein is available in the cells of neurons. These inclusions are known as Lewy bodies. The axons and dendrites present within the Lewy body are known as Lewy neurites. Dissection of the affected brain exhibited Lewy bodies in the olfactory region, gut nervous system, and medulla oblongata starting from the initial stage to progressed PD phases. A Lewy body is found in the cortex and limbic region in late episodes of PD. Recent treatments are manifested by levodopa, which escalates the synthesis of dopamine. It provides relief from bradykinesia and tremor (Connolly and Lang 2014). However, it has a significant disadvantage of the “on–off” phenomenon. Thus, the efficacy of levodopa is likely to be decreased, causing degradation of levels of dopamine and affecting its neurotransmission. Levodopa is also not effective for non-motor problems and impairments (Albin and Leventhal 2017; Zhai et al. 2019). The death of neurons of dopamine and the production of Lewy bodies are not prevented by levodopa. The detection of motor problems is exhibited at a very later stage when already there is an immense loss of neurons of dopamine in the synaptic terminal (Olanow 2019). Brain dissection manifested that the degradation of axons in the synaptic end starts long before the dopamine neurons start degrading (Kordower et al. 2013). Thus, the causes of presynaptic dysfunction in PD may help us develop remedies and mitigations to restore the function of the synapses at the terminal end.
12.2 Studies Used to Demonstrate Presynaptic Dysfunction in PD 12.2.1 Imaging Study PD mainly focuses on the expiration of neuronal dopamine in the synaptic terminal. So, dopamine loss at the terminal end and striatum axons can be targeted for therapeutic purposes (Kordower and Burke 2018; Wong et al. 2019). The theory has been concluded because of the diminished localization of the neurons in the dopamine terminals of the striatum. Research evidence proved that the loss of pre-synapse at the terminal end causes PD and dopaminergic neurons to be deprived. A positron emission tomography imaging study was used to show that hyposmia and low levels of dopamine have given rise to PD (Jennings et al. 2017). High-resolution imaging was performed by nortropane very recently to analyze the presynaptic terminals in human brains containing dopaminergic neurons (Delva et al. 2020). The degradation of synapses was detected by a marker called [11C]-UCB-J, which exhibited synaptic loss at the neuron terminals (Matuskey et al. 2020). This study concluded that the abnormalities that arise at the presynaptic terminal are due to the prognostication of the axonal neurons in the striatum (Delva et al. 2020). There is a limitation of imaging studies because a single marker is scanned singly (Janz and Südhof 1999). Further findings will be required to discover markers to differentiate between dopamine loss and that of synaptic vesicles. In the present
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scenario, research is executed to discover multiple synaptic markers of PD that will allow better resolution.
12.2.2 Pathological Study Pathological studies manifested that dopamine is degraded at the onset of PD. Immuno-staining helps in detecting the degeneration in the brain caused by PD. It was concluded in a study that dopamine loss at the presynaptic terminal end has a connection with dopamine loss in the neurons (Kordower et al. 2013). It was executed in vivo in the knockout rat. The α-synuclein was inoculated to the striatum resulting in the development of additions which was identical to those discovered in PD patients’ brains (Thomsen et al. 2020). This study was further confirmed by immunohistochemistry. Though neuronal deprivation is thought as the primary characteristic of Parkinson’s, the neurons containing glutamate are also altered in the striatum. Glutamate terminals are present in the striatum, cortex, and dendritic spines. Histopathological studies manifested that the density of the spine tends to diminish in advanced patients, leading to the loss of glutamate-containing synapses (Villalba and Smith 2018). The dopamine level reduces glutamate-containing synapses and dendritic spines are lost in early PD with minimum loss of dopamine (Paillé et al. 2010). This loss of glutamate-containing synapses produces impairment in networking (Foffani and Obeso 2018). Thus, factors such as glutamate-containing synapses and glutamate- dopamine fusion in the striatum are important for analyzing PD-related mechanisms (Graybiel 2016).
12.2.3 PD and Synaptic Activity Dysfunction of synaptic activity seems to be a significant event in the case of several neurodegenerative diseases, further leading to severe dysfunction (Wishart et al. 2006). Much evidence has pointed out the role of various genes in controlling presynaptic activation in PD. The α-synuclein emancipation executed on knockout rats has shown support for the fact that it has a significant impact on how presynaptic activity is regulated. Similarly, the effect of other factors such as DJ-1, PINK1, and parkin on knockout rats was also studied showing defects in the presynaptic mechanism (Kitada et al. 2009). Different the leucine-rich repeat kinase 2 (LRRK2) models have also exhibited severe defects in neurotransmission (Li et al. 2010). Previous studies were carried out on R1441C LRRK2 knockout rats and transgenic mice. Major impairments were noticed in the stimulation of nigrostriatal dopamine, leading to the deterioration of the membrane. For further investigation, chromaffin cells were isolated from the R1441C LRRK2 knockout rats and exhibited depletion of catecholamine emancipation (Tong et al. 2009). Deficiencies in the release of dopamine and enhanced immunoreactivity were also shown by the G2019S BAC
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knockout rats (Melrose et al. 2010). This study has accentuated the direct effect of LRRK2 on an endocytic molecular mechanism. The rate of endo and exocytosis in the striatum was effectively reduced, which shows the articulation of LRRK2 (Xiong et al. 2010). Thus, it has been concluded that the flogging of vesicles and spatial arrangements in the pool of pre-synapse largely depends on the LRRK2. Different proteins of pre-synapse such as clathrin and actin have in vitro interrelation with LRRK2 (Meixner et al. 2011). LRRK2 not only helps in executing protein–protein interaction but also consists of the kinase domain. Thus, it can be concluded that LRRK2 may have an influence on the trafficking of SV in the following ways: marshaling of SV, SNARE complex dismantlement, and reclaiming of SV. Actin, synapsin, and LRRK2 tend to interrelate with each other. The SV marshaling is intoned by LRRK2 when LRRK2 interacts with actin and synapsin. In dictyostelium, the protraction of the filament is impeded by the phosphorylation of actin (Liu et al. 2006). Therefore, the SV marshaling can be regulated by the stability of the actin filament. SV2A is considered to be one of the most potent interactors of LRRK2. This protein is involved in the calcium exocytosis process and is present in the neurons of the endocrine cells (Chang and Sudhof 2009). SV2A interrelates with synaptotagmin by negative exocytosis of calcium and positive phosphorylation of SV2A (Pyle et al. 2000). LRRK2 also tends to bind with the NSF complex which causes the dismantling of the SNARE complex. NSF undergoes phosphorylation that wards off the intercalation with α SNAP (Fig. 12.1). LRRK2 also intercalates with dynamin, clathrin, and AP complex. These proteins are inculpated in the modulation of phosphorylation and endocytosis of SV. Dynamin undergoes phosphorylation that diminishes its binding with clathrin, leading to the impairment of clathrin vesicle formation. Both the chains of clathrin and AP complex sustain phosphorylation producing a degradative effect. Thus, it causes endocytosis by undergoing phosphorylation with the interactors. Rab5 is considered to be the main regulator in the endocytosis of vesicles. It interacts withLRRK2 causing over-expression that balances the over-expression of LRRK2, which is mainly responsible for its defect in endocytosis.
Fig. 12.1 Impact of LRRK2 on the trafficking of the vesicle at the presynaptic site
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12.3 Mechanisms Involved in Presynaptic Dysfunction 12.3.1 Axon Ramification on Synaptic Deprivation The morphology of the axon greatly affects the accountability of neurons in PD (Gonzalez-Rodriguez et al. 2020). Especially, arborization is mainly caused by dopamine neurons. The dopamine is released in the axon of the rat at a rate of 2–6 × 105 (Matsuda et al. 2009). There are millions of release sites of dopamine. Noradrenergic neurons, serotonergic neurons, cholinergic neurons, and pedunculopontine neurons are also endangered in PD followed by arborization (Del Tredici and Braak 2016). This concept was reinforced by the fibrillar injection into the brain. It consists of various neurotransmitters such as GABA and glutamate. After fibrillar injection into the cholinergic neurons, α-synuclein inclusions were formed. When the arborization of the axons of dopamine neurons is expanded, their propensity to toxins increases. This explores the idea that the enormous branching of axons leads to amenability (Giguere et al. 2019). This enormous arborization of axons causes huge stress on these neurons’ metabolism. Escalation of phosphorylation produces a large number of reactive oxygen species. When the dopamine neuron’s arborization is diminished, levels of phosphorylation and ROS are also decreased. The aggregation of α-synuclein leads to the escalation of oxidative stress in neurons of dopamine (Di Maio et al. 2016). This incident is responsible for causing damage to the mitochondria and synapses. The neurons exposed to the arborization of the axon also fluctuate the concentration of intracellular Ca2+. The protease cleaves the fibril of α-synuclein at the C-terminus. α-synuclein is fibrilized by calpain. This leads to the deterioration in the lysosomes, resulting in the aggregation of α-synuclein and blocking its transport mechanism. The mitochondria decayed greatly with continuous arborization, causing a formation of toxins in the synapse. Thus, it can be concluded that the neurons containing branched axons and having escalated metabolic burden are highly at risk and may manifest toxicity of the synapse.
12.3.2 α-Synuclein Aggregate Formation In PD, α-synuclein significantly contributes to synaptic dysfunction (Ghiglieri et al. 2018). It is located at the end of the pre-synapse. α-synuclein consists of the domain of non-amyloid components. But it is not manifested in the brain. Additionally, the cholinergic neurons have α-synuclein. The defect in that region may cause sleep, attention, and cognition problems. It is manifested at the GABAergic terminal, but it exhibits very little overlying with the markers of GABA. Its exact role is unknown but no over-expressed phenotypes are seen in the mice with α-synuclein. Sometimes it is necessary to diminish the levels of neuronal α-synuclein. Antisense oligonucleotides cause the depletion of synapses (Murphy et al. 2000). The study was first executed in knockout rats. The restraining of the synaptic vesicles is also enhanced at the terminal end (Vargas et al. 2017). Recently,
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a study has been executed with vesicle-associated membrane protein 2 (VAMP2) and α-synuclein. The membrane and synaptic vesicle are fused with the assistance of VAMP2. When the binding region is deleted, the congregating of the synaptic vesicles can be prevented. Thus, it can be said that α-synuclein clusters cease or control the secretion of synapses. The interaction between α-synuclein and DAT causes a diminution of DAT (Lee et al. 2001). This is another mechanism by which α-synuclein diminishes the dopamine level in the striatum (Giordano et al. 2018). Mutations may occur in α-synuclein and the specific gene causing polymorphisms (Spillantini et al. 1997). Antibodies like ubiquitin or stains like hematoxylin were used to identify LBs. This led to the evolution of modified antibodies and it was also found that α-synuclein modifications were found only in the affected brains. The modified antibodies can detect the aggregation of Lewy neurites. They are more abundantly found in the brain. They are visible more clearly than LBs, which has been confirmed by staging studies. Neurons of the hippocampal region when exposed to α-synuclein fibrils also diminish the density of the spines. This proves the phenotypic property of the synaptic loss. Neurons containing fibrils and devoid of α-synuclein do not exhibit loss of the dendritic spine. This supports the fact that loss of synapse occurs because of the degradation of α-synuclein. When neurons of the hippocampal region are exposed to fibrils of α-synuclein, the frequency of postsynaptic potential is significantly increased. The synaptic density is diminished due to the loss of density of the spine. Therefore, when the postsynaptic potential is increased, it leads to enhanced exocytosis. Further research is required to support this phenomenon. The potentiation of LTP is defective due to the aberrant aggregation of α-synuclein. This takes place through the diminution of the expression of NMDA receptors (Tozzi et al. 2016). The neuronal tone is also reduced because of the diminished NMDA receptor expression. Spectrin is a type of actin protein that has cross-linking properties. It targets the NMDA receptors on the surface of the cell. The α-synuclein tends to react with this spectrin protein because of which NMDA receptors are degraded due to the aggregation of α-synuclein. Fibril-instigated α-synuclein aggregates when produced early also cause loss of neuronal activity and decreased transport of calcium. These disruptions in neuronal activity are responsible for cognitive dysfunction in PD.
12.3.3 Mutation of Leucine-Rich Repeat Kinase 2 In this chapter, we focus on the specific synapse on which LRRK2 will be acting in the brain. LRRK2 undergoes vigorous mutations, which may be the main reason for PD. Mutation in the G2019S gene is very common (Trinh et al. 2014). The LRRK2 polymorphism is autosomal-dominant and is usually seen in late PD (West et al. 2014). Many investigations using LRRK2 expression in dopamine neurons have been conducted, with varying degrees of success. The result depicted a minuscule degree of manifestations in the rat’s brain. Much research is required to establish the manifestations in the brain. However, the manifestation of LRRK2 in the basal
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ganglia has been confirmed and its role in the regulation of motor functions has also been established. The manifestations of LRRK2 in the neurons of dopamine are quite difficult to encounter. Transgenic knockout rats overexpress LRRK2. However, aged G2019SLRRK2 rats exhibited a low level of dopamine. Recently, G2019S knockout rats were used to execute this study. Since transgenic animals show a higher degree of mutation and expression, they are widely used. So, it can be said that knockout rats can express the effect of mutation more effectively in humans where LRRK2 is not expressed completely. G2019S knockout rats aged 6 months were analyzed by micro-dialysis, which determines the dopamine level in the striatum (Volta et al. 2017). The rats manifested a normal dopamine level. But when 12-month-old rats were taken, they exhibited low levels of dopamine. Much research was conducted to establish the significance of LRRK2 in glutamic synapses. Neurons extracted from G2019S rats exhibit an escalation in the frequency of EPSC in comparison to the neurons extracted from the wild rats where there were no changes in the frequency of EPSC. The result of this study concluded that when the activity of LRRK2 kinase was escalated, glutamic activity was also enhanced in the striatum. Many reports suggested that this activity was dependent on potential and was insensitive to tetrodotoxin (Volta et al. 2017). They also exhibit normal EPSC frequency. The presence of Ca2+ ions at the terminal end of the pre- synapse may be another reason (Tozzi et al. 2018). Recently, both LRRK2-R1441C and LRRK2-G2019S knockout rats were used for a study. They both showed reduced frequency of EPSC. Their mutation leads to the escalation of the protein kinase A activity in the post-synapse. This increases GluA1 targeting in neurons with an increase in glutamate currents. Further research is required to study the effect of LRRK2 on the neurons in case of very low dopamine in the striatum (Graves and Surmeier 2019). Calcium ions induce potential to the terminal end of the presynaptic membrane. As a result, synaptic vesicles fuse with the plasma membrane, releasing neurotransmitters into the vicinity of the synapse. Various mechanisms such as endocytosis by clathrin, bulk, and ultra-fast endocytosis help in the redeeming of synaptic vesicles. In clathrin-endocytosis, the coating of clathrin is removed and the synaptic space is filled with neurotransmitters. The vesicles undergo exocytosis (Gan and Watanabe 2018). LRRK2 takes part in both exocytosis and endocytosis of the synaptic vesicle. LRRK2 undergoes phosphorylation with Rab3a (Steger et al. 2016). It is concentrated at the terminal of the presynaptic end. It helps in the regulation of the secretion of vesicles. Auxilin is also phosphorylated by LRRK2 (Nguyen and Krainc 2018). They cause endocytosis of synapses. Hence, it may be inferred that LRRK2 significantly contributes to elevating the kinase activity in the synaptic vesicle (Fig. 12.2).
12.3.3.1 Mutation of VPS35 VPS35 mutation is also responsible for causing phenotypic PD, especially sporadic Parkinson’s. It is regarded as one of the main contributors to the occurrence of PD
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Fig. 12.2 LRRK2 (red) is manifested enormously in the neurons of the cortex of a rat (West et al. (2014)
genetically. VPS35-VPS29 and VPS26 lead to the formation of a complex that is associated with the transport mechanism of the membrane from the endosomes to Golgi bodies. VPS35 is also present in the polarized form of neurons that helps the AMPA receptors to target the dendritic spine of the plasma membrane (Temkin et al. 2017). It also causes permanent impairment of the synapses. The D620N- VPS35 knockout rats were dissected first to analyze the consequences. Knockout rats of age 13 months were considered for the study. The study manifested damage in the axon, striatum, and hippocampus. Hence, the above findings suggest that mutations in VPS35 may cause presynaptic damage.
12.3.3.2 Mutation of Synaptic Genes Inherited genes are responsible for PD, especially sporadic Parkinson’s. The recessive gene’s mutations are also considered to be a major reason for PD. Both these genes are associated with idiopathic PD, differences in gait, body stiffness, tremors of different parts of the body, and dopamine loss in the neurons. Mutations in the recessive gene cause slower advancement of the disease. Therefore, it poses a lower risk to patients with PD. Recessive genes can manifest some extra symptoms such as seizures, pyramidal symptoms, and certain disabilities. The patients with PD due to this factor are devoid of Lewy bodies (Schneider and Alcalay 2017). However, the tissue quality has deteriorated in those patients. Different mutation types lead to impaired function (Dawson and Dawson 2010). This kind of mutation is commonly seen in patients under 45 years of age. A symptom-like disturbance of gait is quite common. However, the disease progression is very slow. Dystonia and dyskinesias are also very common. Endophilin A1, dynamin, and synaptojanin 1, among other parkin proteins, are connected to the endocytosis of synaptic vesicles (Cao et al. 2014). Dopamine loss in the neurons is not present in parkin knockout animals but exhibits escalation of dopamine levels in the brain. Microdialysis revealed that older parkin knockout rats have diminished glycine secretion. So, it can be said that parkin mutation influences motor behavior. This mechanism occurs when the transference of glutamine occurs in the brain.
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The clathrin-coated vesicles become uncoated when auxilin binds to HSC70. Auxilin mutation leads to the reduction of the level of protein. This mutation produces symptoms like instability of posture and slow movement. Neurodevelopment is also delayed followed by epilepsy and pyramidal affliction. In neurons of rats, clathrin-coated vesicles accumulate if auxilin is not expressed (Yim et al. 2010). Moreover, LRRK2 undergoes phosphorylation along with the auxilin clathrin domain, demonstrating the concomitant endocytosis of synaptic vesicles. To commence the unification of auxilin and clathrin uncoated vesicles, synaptojanin 1 undergoes dephosphorylation along with the endocytic vesicles. Synaptojanin 1 mutation causes the onset of PD symptoms such as disturbances of gait and stiffness of the body, followed by slow movement. It exhibited poor levodopa receptiveness and atrophy of the cortex. Rats lacking synaptojanin 1 displayed aberrant dopamine release in the striatum (Cao et al. 2017). When manifestation of synaptojanin 1 occurs, it causes impairment of endocytosis of synaptic vesicles in the neurons of the midbrain, which suggests repercussions on the neurons. Consequently, dopamine neurons are vulnerable to synaptic abnormalities although recessive gene mutations result in the encoding of synaptic proteins that may not be the etiology of PD.
12.3.4 Presence of Risk Genes The presynaptic end is an essential location for several risk genes. Finding the risk genes in neurons involves gene analysis by phenotypic trait and cell-type patterns. However, the cell-type mutant changes in the gene remain obscured because of some technical challenges. Some variations, like SH3GL2, have an impact on the genetic makeup of the brain, causing synaptic dysfunction and endocytosis trafficking. Researchers make use of the relationship between the malfunction of α-synuclein and the genes that cause PD because α-synuclein is crucial for the health of synapses in both healthy individuals and those with the disease. Synucleinopathy is a very typical PD symptom. Single-cell characterization (Saunders et al. 2018) was used to inspect the connection between the neurons and the risk genes. The analysis determined that Sh3gl2 expresses the in the presynaptic terminal end. Sh3gl2 consists of neurons containing glutamate, but devoid of neurons containing dopamine. The anatomical distribution of Sh3gl2 and Lrrk2 was studied in the brain of rats. Sh3gl2 is expressed in the neurons containing glutamate more clearly compared to that of the Lrrk2. This is because of the selective localization of LRRK2 in the neurons. LRRK2 mutation changes the function of the glutamate at the synaptic terminal (Chen et al. 2020). Future research is required to find out whether the fusion of LRRK2 and abnormal α-synuclein leads to the impairment of secretion of GABA at the presynaptic terminal and causes the diminishing of dopamine in the striatum. Genes such as Sh3gl2, Synj1, and Lrrk2 are present vividly in the presynaptic neurons along with neurons containing dopamine. So, the susceptibility of these
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neurons containing risk genes is not assignable to the dysfunction occurring in the neurons containing dopamine. However, further research manifested that the risk genes are more concentrated in the midbrain neurons containing dopamine and cortex neurons containing glutamate (Agarwal et al. 2020). Dopamine is hence susceptible to PD due to a link between risk gene malfunction and dopaminergic neurons’ cell-specific features.
12.4 Conclusion The mechanisms considered in this chapter bestowed impregnable reinforcement for the implication of presynaptic dysfunction about the causes of PD. Imaging and laboratory studies manifested the presynaptic dysfunction even in the initial phases of PD. The evolution of special ligands helps in the timely detection of Parkinson’s even. Ligands like SVC2B (Janz and Südhof 1999) help in differentiating PD from other neurodegenerative problems. The change of characteristics of synaptic markers present in the spinal fluid also helps in the detection of cognitive abnormalities. The researchers should focus more on the function of synapses. The activity of endophilin in the neurons of glutamate advocated that these neurons can prove to be effective for the investigation of contributions of dysfunction of endophilin to the pathology of α-synuclein. The embellishment of synaptojanin with dopamine and neurons of glutamate advocated that certain mutations are responsible for changing the function of the synapse. This chapter provides insight into how changes in the expression or function of the risk gene trigger certain symptoms in PD and also points out the mechanisms that will prevent the alleviation by levodopa.
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Tong Y, Pisani A, Martella G, Karouani M, Yamaguchi H, Pothos EN, Shen J (2009) R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proc Natl Acad Sci U S A 106:14622–14627 Tozzi A, de Iure A, Bagetta V, Tantucci M, Durante V, Quiroga-Varela A et al (2016) α-Synuclein produces early behavioral alterations via striatal cholinergic synaptic dysfunction by interacting with GluN2D N-methyl-D-aspartate receptor subunit. Biol Psychiatry 79:402–414. https:// doi.org/10.1016/j.biopsych.2015.08.013 Tozzi A, Tantucci M, Marchi S, Mazzocchetti P, Morari M, Pinton P et al (2018) Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson’s disease. Cell Death Dis 9:204. https://doi.org/10.1038/s41419-017-0221-2 Trinh J, Guella I, Farrer MJ (2014) Disease penetrance of late-onset parkinsonism: a meta-analysis. JAMA Neurol 71:1535–1539. https://doi.org/10.1001/jamaneurol.2014.1909 Vargas KJ, Schrod N, Davis T, Fernandez-Busnadiego R, Taguchi YV, Laugks U et al (2017) Synucleins have multiple effects on presynaptic architecture. Cell Rep 18:161–173. https://doi. org/10.1016/j.celrep.2016.12.023 Villalba RM, Smith Y (2018) Loss and remodeling of striatal dendritic spines in Parkinson’s disease: from homeostasis to maladaptive plasticity? J Neural Transm 125:431–447. https://doi. org/10.1007/s00702-017-1735-6 Volta M, Beccano-Kelly DA, Paschall SA, Cataldi S, MacIsaac SE, Kuhlmann N et al (2017) Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice. eLife 6:e28377. https://doi.org/10.7554/ eLife.28377 West AB, Cowell RM, Daher JP, Moehle MS, Hinkle KM, Melrose HL et al (2014) Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. J Comp Neurol 522:2465–2480. https://doi.org/10.1002/cne.23583 Wichmann T (2019) Changing views of the pathophysiology of Parkinsonism. Mov Disord 34:1130–1143. https://doi.org/10.1002/mds.27741 Wishart TM, Parson SH, Gillingwater TH (2006) Synaptic vulnerability in neurodegenerative disease. J Neuropathol Exp Neurol 65:733–739 Wong YC, Luk K, Purtell K, Burke Nanni S, Stoessl AJ, Trudeau LE et al (2019) Neuronal vulnerability in Parkinson’s disease: should the focus be on axons and synaptic terminals? Mov Disord 34:1406–1422. https://doi.org/10.1002/mds.27823 Xiong Y, Coombes CE, Kilaru A, Li X, Gitler AD, Bowers WJ, Dawson VL, Dawson TM, Moore DJ (2010) GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet 6:e1000902 Yim YI, Sun T, Wu LG, Raimondi A, De Camilli P, Eisenberg E et al (2010) Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice. Proc Natl Acad Sci U S A 107:4412–4417. https://doi.org/10.1073/pnas.1000738107 Zhai S, Shen W, Graves SM, Surmeier DJ (2019) Dopaminergic modulation of striatal function and Parkinson’s disease. J Neural Transm 126:411–422. https://doi.org/10.1007/ s00702-019-01997-y
Mitochondrial Dysfunction and Its Role in Neurological Disorders
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Gulzar Ahmed Rather, Vishal Mathur, Muzafar Riyaz, Raman Yadav, Anima Nanda, Arif Jamal Siddiqui, Mashoque Ahmad Rather, Andleeb Khan, and Sadaf Jahan
Abstract
Mitochondria, pivotal cell organelles recognized for their paramount role in cellular energy production, play a crucial part in neurological disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and multiple sclerosis when their functionality falters. Among the repercussions of mitochondrial dysfunction, neuroinflammation emerges as a prominent concern, eliciting an upsurge in G. A. Rather · A. Nanda Department of Biomedical Engineering, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India V. Mathur Department of Pharmaceutical Chemistry, School of Pharmaceutical Chemistry, Jamia Hamdard, New Delhi, India M. Riyaz Xavier Research Foundation, St. Xavier’s College, Palayamkottai, Tamil Nadu, India R. Yadav Department of Pharmacology, Sri Ramachandra Medical College and Research Institute, SRIHR, Chennai, Tamil Nadu, India A. J. Siddiqui Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia M. A. Rather Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA A. Khan Department of Biosciences, Faculty of Science, Integral University, Lucknow, India S. Jahan (*) Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Al Majmaah, Saudi Arabia e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_13
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the generation of reactive oxygen species (ROS). The deleterious effects of these ROS on nerve cells induce a cascade toward neurodegeneration. This chapter comprehensively delves into the adverse implications of mitochondrial dysfunction on the advancement of diverse neurological ailments, with particular emphasis on the pivotal role of neuroinflammation. Keywords
Neuroinflammation · Mitochondrial dysfunction · Parkinson’s disease · Alzheimer’s disease · Reactive oxygen species
13.1 Introduction Mitochondria, often known as the “powerhouses of the cell,” performs an essential role in the production of cellular energy and a wide range of other cellular processes (Ernster and Schatz 1981; Chinnery and Schon 2003). These dynamic organelles contain their own copy of the genetic material and participate in important metabolic processes. On the other hand, mitochondrial dysfunction is a disorder linked to a wide range of illnesses and abnormalities in the physiology of the organism. This dysfunction occurs when the mitochondria’s regular functioning is interrupted (Brand and Nicholls 2011; Pieczenik and Neustadt 2007). The malfunctioning of mitochondria may have significant repercussions at the cellular, tissue, and even systemic levels. At the cellular level mitochondrial dysfunction can negatively impact energy production, disrupts cellular signaling, and hinder the apoptotic process. The imbalance results in the vulnerability of cells. Consequently, malfunctioning mitochondria render cells more vulnerable to harm and death (Lemasters et al. 1999; Eckert et al. 2003), specifically the cells that rely on mitochondria for energy and functioning viz. brain, heart, and muscles. Furthermore, those affected tissues collectively impact the organelle’s anatomy and physiology, leading to compromised health and metabolic disorders. Associated diseases are listed in Fig. 13.1 (Nicolson 2014). Mitochondrial dysfunction may have several causes, some of which are genetic while others are environmental. Mutations in nuclear DNA encoding mitochondrial proteins, or mt-DNA mutations, are important contributors (Johri and Beal 2012). A reduction in ATP (adenosine triphosphate) synthesis and an increase in the production of reactive oxygen species (ROS) may come from inherited or acquired mutations affecting the electron transport chain (ETC) (Nicolson 2014). Pollution, drug use, prolonged stress, and poor lifestyle choices have all been linked to mitochondrial dysfunction (Myhill et al. 2009; Declerck et al. 2015). Mitochondrial malfunction is a characteristic of aging and is associated with several chronic conditions. Hereditary or basic mitochondrial defects are known to impact subsequent or inherited degenerative disorders (Johns 1995; Vafai and Mootha 2012).
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Fig. 13.1 Chronic illnesses related to mitochondrial dysfunction
13.1.1 Molecular Aspects of Mitochondrial Dysfunction The double-membraned organelles referred to as mitochondria, serve a vital role in maintaining cellular stability. However, molecular-level mitochondrial malfunction may have far-reaching consequences for a variety of cellular functions, ultimately leading to a spectrum of human disorders (Nicolson 2014; Rehman et al. 2023). Mitochondrial malfunction may result from a deficiency in the number of mitochondria, an inability to provide the necessary substrates for mitochondria, or issues with the electron transport chain or the ATP generation machinery. Mitochondrial membrane depolarization, transcriptional activation, and other processes can alter the number and functional status of mitochondria within a cell through various mechanisms (Lee et al. 2012; Twig and Shirihai 2011; Priault et al. 2005). These mechanisms include fission, the creation of new mitochondria, the elimination and complete degradation of dysfunctional mitochondria, and mitophagy.
13.1.1.1 Mitochondrial DNA Mutations Mutations in mitochondrial DNA (mtDNA) are a major cause of mitochondrial malfunction. Mitochondria possess their own compact circular DNA that encodes crucial proteins vital for energy production. Due to its closeness to the ROS generated during oxidative phosphorylation, mtDNA is susceptible to damage (Chinnery et al. 2002). Mutations in mtDNA may compromise mitochondria’s ability to produce the necessary proteins vital for proper functioning. Certain mtDNA mutations have been linked to mitochondrial illnesses such as Leigh syndrome and mitochondrial encephalomyopathy (Bannwarth et al. 2013).
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13.1.1.2 Oxidative Stress and Reactive Oxygen Species (ROS) Mitochondria are both a source and a target of ROS. While ROS are natural byproducts of mitochondrial respiration, excessive ROS production can cause oxidative stress, leading to mitochondrial dysfunction (Wang et al. 2014; Islam 2017). ROS can directly damage mitochondrial proteins, lipids, and mtDNA, further exacerbating the problem. The impairment of mitochondrial proteins involved in oxidative phosphorylation and antioxidant defense mechanisms can disrupt energy production and increase oxidative damage (Mandelker 2008). Mitochondrial malfunction caused by oxidative stress has been linked to a number of illnesses and ailments, including dementia and cardiovascular issues (Trushina and McMurray 2007). 13.1.1.3 Impaired Mitochondrial Biogenesis The coordination of mitochondrial biogenesis, an intricate process that involves replication of mtDNA, synthesis of mitochondrial proteins, and development of the respiratory chain complexes, is necessary for maintaining mitochondrial function (Sheng et al. 2012). Dysfunction of the mitochondria may come from disruption of this closely controlled mechanism. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1), nuclear respiratory factors, and mitochondrial transcription factor A (TFAM), which are important players in mitochondrial biogenesis, are crucial for preserving mitochondrial integrity (Singulani et al. 2020). These components’ dysregulation, which is often linked to aging and metabolic diseases, may limit mitochondrial biogenesis and ultimately cause malfunction (Wang et al. 2019). 13.1.1.4 Mitochondrial Dynamics Mitochondria are very active organelles that continually evolve via a series of fusion and fission events. These processes are essential for maintaining mitochondrial quality control, distribution, and turnover. Imbalances in mitochondrial fusion and fission can disrupt the delicate equilibrium of mitochondrial function (Suárez- Rivero et al. 2016). Excessive fission can result in fragmented and dysfunctional mitochondria, impairing energy production and triggering apoptotic pathways (Ni et al. 2015). However, problems with fusion might degrade mitochondrial quality control systems and impede the interchange of mitochondrial components. Dysfunctional mitochondrial dynamics have been implicated in neurodegenerative diseases, cardiovascular disorders, and metabolic syndromes (Wada and Nakatsuka 2016). Understanding the intricate mechanisms underlying mitochondrial dysfunction is crucial for developing targeted therapeutic strategies to mitigate the consequences of impaired mitochondrial function and pave the way for potential interventions in the treatment of mitochondrial diseases and associated conditions. Continued research in this field holds promise for uncovering novel molecular targets and approaches to preserving the vital functions of mitochondria within our cells.
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13.1.1.5 Inflammation: A Double-Edged Sword The inflammatory response of the active immune system is essential for warding off pathogens, harmful chemicals, and other invaders. Different molecular mediators, such as cytokines, chemokines, and prostaglandins, work along with immune cells, including neutrophils, macrophages, and lymphocytes, to accomplish this. According to research by López-Armada et al. (2013), acute inflammation is a short-lived, localized process that aids in tissue repair and equilibrium restoration. Persistent or chronic inflammation, however, has been linked to the development of a wide range of illnesses, including autoimmune disorders, cardiovascular diseases, and neurodegenerative disorders (van Horssen et al. 2019).
13.1.2 Neuroinflammation The inflammatory response is a multifaceted physiological process that aids in the body’s defense against harmful stimuli and speeds up the healing of damaged tissues. The central nervous system (CNS) is especially vulnerable to the negative consequences of inflammation when it is out of control or persists for long periods. The CNS inflammatory response, or neuroinflammation, is a complex process that involves many different cell types and chemical mediators (Lyman et al. 2014). Dysfunctional mitochondria are thought to play a crucial role in the etiology of several neurological diseases, including multiple sclerosis, Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke (Picca et al. 2020). A chain reaction of cellular and molecular processes occurs during neuroinflammation. Microglia are immune cells that live in the CNS, and they play a significant role in both the genesis and control of inflammation (DiSabato et al. 2016). A change to an active phenotype and the production of pro-inflammatory mediators are hallmarks of microglial activation, which expedites neuronal injury. The numerous kind of glial cells in the CNS, astrocytes, play a role in neuroinflammatory processes by regulating immune responses and preserving tissue homeostasis. Alterations in neurotransmitter balance and breakdown of the blood-brain barrier are only two of the many effects of neuroinflammation that may have a negative effect on neuronal function and integrity (Chen et al. 2016). AD, PD and multiple sclerosis are among the major neurological disorders that cause neuroinflammation (Chen et al. 2016). Chronic neuroinflammation aids in disease development and worsens neuronal damage in these states. For instance, the deposition of amyloid-beta plaques in AD causes a chronic inflammatory response, which exacerbates neuronal dysfunction and cognitive impairment. Developing effective treatment options to modulate the inflammatory response and attenuate disease progression, a thorough understanding of the function of neuroinflammation in these illnesses is essential. Because of mitochondrial dysfunction and neuroinflammatory processes, more ROS are formed, which are toxic to neurons. There is a growing recognition that neuroinflammation contributes to neurodegenerative diseases (Chen et al. 2016; Shabab et al. 2017).
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13.1.3 Role of Mitochondrial Dysfunction and Neuroinflammation 13.1.3.1 Mitochondrial Dysfunction-Induced Neuroinflammation The complicated processes of inflammation and neuroinflammation have a significant impact on human health and illness. Chronic or dysregulated inflammation may contribute to the etiology of several illnesses, including CNS problems, while acute inflammation acts as a necessary defense mechanism. Complex cellular and molecular interactions that affect neuronal function and survival are at the heart of neuroinflammation. Witte et al. (2010) investigates the complex interplay between mitochondrial failure, neuroinflammation, and the onset of neurodegenerative disorders. It draws attention to the growing body of research demonstrating that mitochondrial dysfunction is pivotal in starting and maintaining neuroinflammatory responses, which in turn contribute to the development of neurodegenerative diseases. Oxidative stress, the accumulation of mutations, reduced biogenesis, and altered dynamics are all major contributors to mitochondrial dysfunction. These mitochondrial defects interfere with cellular energy metabolism, boost ROS generation, and set off inflammatory signaling pathways. Therefore, neuroinflammation occurs due to the production of cytokines, chemokines, and other mediators by activated immune cells like microglia and astrocytes. A number of researchers have emphasized the two-way connection between mitochondrial failure and neuroinflammation. One way in which mitochondria are damaged is via the release of inflammatory mediators brought on by neuroinflammation. However, mitochondrial failure causes energy deficiencies, ROS production, and damage-associated molecular patterns (DAMP) release, all of which initiate inflammatory responses and keep neuroinflammation going. Mitochondrial failure and neuroinflammation interact with a number of neurodegenerative disorders, such as AD, PD, and amyotrophic lateral sclerosis (ALS). Therapeutic approaches that address both neuroinflammation and mitochondrial dysfunction are highlighted as possible solutions to these diseases.
13.1.4 Associated Neuronal Complication with Mitochondrial Signaling Function and Neuroinflammation Inflammation is triggered by both pathogen-associated molecular patterns (PAMPs) and DAMPs. Pathogen recognition receptors (PRRs) use intracellular signaling pathways to generate molecules involved in recognizing PAMPs and DAMPs. Since mitochondria are similar to bacteria, their leaking contents may trigger the innate immune system by acting as a PAMP or DAMP in the cytosol or extracellular space. Signals of inflammation are controlled by mitochondria. Inflammation caused by mitochondrial leaking Circular DNA and CpG patterns are seen in mitochondria because of ancient eukaryotes endosymbiosis with proteobacteria. NF-κB is triggered by TLR9 when CpG patterns in circular DNA are unmethylated. During cell death, oxidized mtDNA binds to the NLRP3 inflammasome,
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activating it and increasing interleukin-1 (IL-1) beta production. Recognition of mtDNA triggers the production of interferons-1 (IFN-1) through the IRF3 and NF-κB branches of the stimulator of interferon genes (STING) pathway, which is located in the cytoplasm. Mitochondria, like prokaryotes, employ 22 transfer ribonucleic acid (tRNA)s and 2 mitochondrial ribosomes to synthesize peptides containing formyl-methionine (formyl-Met) at the N-terminus. Exposed mitochondrial formyl-Met draws neutrophils outside of cells (Dahlgren et al. 2016), and formylpeptides activate neutrophil FPR signaling by binding to FPRs. Testing shows that fMLP significantly accelerates PI3K-NF-κB activity and IL-1 generation. Approximately 20% of the inner mitochondrial membrane is composed of the phospholipid known as cardiolipin. This particular phospholipid is present in the membranes of all bacterial cells, but it is unique to the inner mitochondrial membrane of eukaryotic cells. The noncovalent effects of cardiolipin may be shown in mitochondrial dynamics, apoptotic signals, mitophagy, and the production of ROS. Cardiolipin causes the release of IL-1 by binding directly to the NLRP3 inflammasome on the outer mitochondrial membrane. Exogenous cardiolipin stimulates mitophagy via binding to the autophagy receptor LC3. The nucleotidases CD39 and CD73 are generally responsible for the fast degradation of extracellular ATP. The production of IL-18 by macrophages is accelerated by acute extracellular ATP exposure, which promotes P2X7 receptor binding and NLRP3 inflammasome activation (Amores-Iniesta et al. 2017). Acute lung injury in mice leads to a transient increase in ATP levels due to LPS-mediated inflammation. Apyrase reduces inflammation caused by lipopolysaccharide. Cytochrome C (Cyt C) in the inner mitochondrial membrane shuttles electrons between complexes III and IV of the ETC. Cyt C in the cytosol binds to Apaf-1 to start the apoptotic process, but its role in the extracellular milieu is less apparent. Inflammation may be affected by cytokine C. Cyt C inhibits IL-12 production by CD8+ dendritic cells (Eleftheriadis et al. 2016). Extracellular Cyt C is lethal to lymphocytes, however, leucine-rich α-2 glycoprotein 1 (LRG1) mitigates its effects (Codina et al. 2010). Cyt C outside the cell may similarly stimulate NF-κB. The role of peripheral inflammation in PD etiology and its possible connection to inflammation in the brain during neurodegeneration. Macrophage microglial cells are the body’s first line of defense against pathogens; they sense and respond to cellular stress and injury by releasing cytokines and ROS. When mitochondrial ROS transmits danger signals into intracellular or extracellular compartments, inflammation is initiated. Pattern recognition receptors (PRRs) are responsible for detecting DAMPs like mtDNA. It is becoming more apparent that circulating mtDNA may be responsible for germ-free inflammation by acting as a DAMP molecule that activates innate immunity through toll-like receptor 9 (TLR 9) at the endo-lysosomal membrane. This activation takes place at the endo-lysosomal membrane. The activation of this response occurs in reaction to a danger that is not generated by a disease. It is possible that ROS generated by mitochondria might trigger sterile inflammation by activating the pathway that includes the NLR family pyrin domain containing 3 (NLRP3) inflammasome and interferon genes. When Procaspase-1 and apoptosis- associated speck-like protein containing a CARD (ASC) are combined, they result
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in the production of a multidomain protein complex. Upon activation, these protein complexes disassemble to release IL-1 and IL-18 in their active forms. Pyroptosis may be caused by holes in the plasma membrane, which might be activated by activating the pathway of the NLRP3 inflammasome. Prolonged activation of the inflammasome may be inflammatory and harmful to tissues by producing intracellular and extracellular DAMPs. When proinflammatory cytokines that were created in the periphery approach the CNS, they have the potential to penetrate the blood- brain barrier and induce neuroinflammation. This occurs when the proinflammatory cytokines connect to microglial receptors in the CNS. A possible feedback loop between neuroinflammation and mitochondrial dysfunction is triggered by ROS signaling. Inflammation brought on by dysfunctional organelles may harm mitochondria, releasing several mitochondrial DAMPs in the process. It is unknown what molecular pathways facilitate the loading of mtDNA into Extracellular Vesicles (EVs) for transit as DAMPs. N-formyl peptides, cardiolipin, TFAM, succinate, and adenosine triphosphate are some of the additional extracellular DAMPs in addition to mtDNA. Cell-free mtDNA and properly functioning mitochondria are present in healthy blood (Nakahira et al. 2011; Julian et al. 2012).
13.1.5 Mitochondrial Dysfunction and Associated Diseases 13.1.5.1 Mitochondrial Dysfunction and AD Microglia and astrocytes become active in AD. Active inflammatory pathways and elevated cytokine levels have been discovered in disease-affected AD brain patients as well as in their serum samples. Inflammation is caused by pathogens, sometimes known as “foreign” agents. Recent research found that mitochondria and/or the components of mitochondria may cause harm and/or mimic the symptoms of diseases. Mitochondrial lysates may cause inflammation in cells, whereas nuclear portions do not. In mouse microglial cells, the amount of mRNA for tumor necrosis factor (TNF), IL-8, and MMP-8 was enhanced when mitochondrial lysates were used. The mRNA levels of the gene TREM2, which suppresses cytokine production, were lower. These changes were brought about as a result of NF-B’s activation of the p38 MAPK signaling pathway. The amount of amyloid precursor protein (APP) mRNA and protein was increased by mitochondrial lysates (Nabi et al. 2022). Amyloid plaques are formed in the brains of Alzheimer’s patients by utilizing the parent peptide, APP, as the building material. Neuroinflammation is caused by mitochondrial lysates, which may also have an effect on the biology of APP. ATP, cardiolipin, TFAM, cytochrome c, formyl peptides, and RNA are all examples of products of mitochondria that are known to have a role in the inflammatory response. Immunogenicity is caused by these chemical substances. There is an ever-growing amount of research that indicates a connection between inflammation and mtDNA. Damage to mtDNA may be caused by oxidative stress, which can then set off astrocyte neuroinflammation (Rather et al. 2021). In mouse primary astrocytes, oxidant-modified mitochondrial polynucleotides cause an increase in the levels of IL-6, MCP-1, IL-1, and TNF. Hydrogen peroxide only damages mtDNA. The
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mitochondrial DAMP molecules were used in the research on the glial cells. Mixed glial cells that have been exposed to ATP produce IL-6 and The chemokine (C-X-C motif) ligand 1 (CXCL1). SH-SY5Y neuroblastoma cells are harmed when they are exposed to human primary microglia media that has been primed with IFN and treated with TFAM (or mitochondrial proteins) (Little et al. 2014). Microglia that have been activated by IFN and TFAM will produce IL-6. It is essential to have a good understanding of neuronal mitochondrial release. Mitochondria that have been discharged by neurons may be found in axon terminals. Glial cells are responsible for the destruction of released mitochondria. This unidentified method could be “transmitophagy,” which is the degradation of mitochondria in several cells. The release of mitochondrial material also occurs during necrosis and necroptosis. Another crucial question is the reason for the release of mitochondrial components by cells. There may be a significant amount of mitochondrial malfunction and inflammation. Inflammation is brought on by malfunction in the mitochondria. There is some evidence that inflammation may alter mitochondria. Mitochondrial dysfunction is the root cause of AD. Mitochondrial dysfunction and neuroinflammation are both possible components of AD (Wilkins and Swerdlow 2016). Mitochondria-based enzymes are less active in AD brains, and the majority of neurons have a lower number of undamaged mitochondria. The fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan reveals decreased glucose utilization in the brain of a patient with AD, which may be linked to mitochondrial dysfunction (Mosconi et al. 2007). In addition to AD, these changes are brought on by aging. Patients with AD had significantly lower levels of Cyclooxygenase (COX), pyruvate, and -ketoglutarate activity than older adults. These changes affect the brain. The cytoplasmic hybrid (cybrid) model, in which platelets are combined with a cell line that does not contain mtDNA, simulates the mitochondrial abnormalities that are seen in AD patients. Recent examinations focused on this approach. Since mtDNA is the only material that can be passed down from generation to generation, it is possible to establish hybrid cell lines with nuclear DNA backgrounds that are identical. Studies using hybrids have shown evidence that mtDNA may be responsible for mitochondrial abnormalities in AD patients. The majority of mtDNA comes from mothers. AD is seen in the kids of mothers more often than it is in those of fathers. Mothers with AD exhibit higher anomalies in brain glucose metabolism before cognitive impairments than fathers with AD (Mosconi et al. 2007). Bioenergetic shifts are a symptom of AD, and these shifts may be more pronounced in those whose mothers had the disease. According to several studies, mitochondrial dysfunction may be an early step in the development of AD. This viewpoint is supported by the fact that certain mitochondrial issues associated with AD are systemic in nature that mtDNA seems to be able to account for at least some of these inadequacies, and that inheritance of mtDNA may have an effect on the chance of developing AD. Although inflammation may upregulate in areas of the body other than the brain in AD patients, this does not suggest that it may explain cybrid results or maternal inheritance bias. Therefore, if mitochondrial dysfunction is the cause of neuroinflammation, the cause may be farther upstream (Soares et al. 2012; Faria
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Fig. 13.2 Mitochondrial inflammation in AD
et al. 2014; Leung et al. 2013). The role of mitochondrial dysfunction in AD is represented in Fig. 13.2.
13.1.5.2 Mitochondrial Dysfunction and Parkinson’s Disease A study examines the link between Parkin, mitochondrial dysfunction, and neuroinflammation in the clinical context of PD. It delves into new research and findings that shed light on the role of Parkin in mitochondrial health, the repercussions of Parkin mutations, and the influence of mitochondrial dysfunction and neuroinflammation on PD etiology (Pereira et al. 2023). The research emphasizes the importance of Parkin, a ubiquitin ligase enzyme, in mitochondrial function and quality control. It controls mitochondrial dynamics, mitophagy (the selective removal of damaged mitochondria), and the clearing of malfunctioning mitochondria (Bose and Beal 2016). Parkin gene loss-of-function mutations have been linked to earlyonset familial PD. These mutations affect Parkin’s capacity to appropriately regulate mitochondrial quality control systems, resulting in a buildup of damaged mitochondria and reduced cellular energy metabolism. Dysfunctional mitochondria result in reduced ATP synthesis, increased ROS formation, and poor calcium homeostasis, all of which lead to neuronal dysfunction and degeneration (Abou- Sleiman et al. 2006). Furthermore, the buildup of damaged mitochondria causes neuroinflammatory responses such as microglial activation and the production of pro-inflammatory cytokines and chemokines. PRRs, are able to identify DAMPs like mtDNA. The concept that free-floating mtDNA works as a DAMP that induces germ-free inflammation and enhances innate immunity by way of toll-like receptor 9 (TLR 9) at the endo-lysosomal membrane is gaining popularity. TLR 9 is located on the endo-lysosomal membrane. Mitochondrial ROS may be the cause of sterile inflammation that is stimulated by the NLRP3 inflammasome and interferon genes pathway stimulator. When
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Fig. 13.3 Mitochondrial inflammation in Parkinson’s disease
Procaspase-1 and ASC are joined, a multidomain protein complex is generated. These protein complexes both breakdown to release their active versions of IL-1 and IL-18 when triggered. Holes in the plasma membrane, maybe caused by activation of the NLRP3 inflammasome pathway, are the likely cause of pyroptosis. Prolonged inflammasome activation has the potential to damage tissues by generating inflammatory DAMPs at both the intracellular and extracellular levels. It is feasible for proinflammatory cytokines to penetrate the blood-brain barrier and make their way into the CNS. These cytokines were created in the periphery of the body. After arriving at their destination, they attach to microglial receptors and activate NLRP3, leading to neuroinflammation. This persistent neuroinflammation aggravates neuronal damage and hastens the course of PD. In response to mitochondrial failure, dysregulated NF-κB signaling results in the continuous activation of microglia and the production of inflammatory mediators. The resultant neuroinflammatory milieu fosters mitochondrial malfunction and neuronal injury in a vicious cycle (Snow and Albensi 2016). PD and mitochondrial dysfunction is represented in Fig. 13.3.
13.1.5.3 Mitochondrial Dysfunction and Down Syndrome (DS) DS is a genetic illness that can lead to problems with thinking, the face, the gut, heart problems at birth, and brain, endocrine, and immune system problems. DS is mostly studied in children and is associated with a decreased lifespan. As a childhood condition, Down Syndrome (DS) can no longer be managed effectively since people are living longer. Patients with DS have accelerated aging compared to age- matched controls (Schoufour et al. 2015). The development of wrinkles, premature greying and loss of hair, eyesight impairments, early menopause, a high prevalence of AD, and multimorbidity are all consequences of accelerated aging (Esbensen 2010). Segmental progeroid syndrome is what DS is. Therefore, discovering the mediators of age-related characteristics might aid in the development of effective treatment techniques for delaying the aging process and increasing longevity (Franceschi et al. 2019).
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A dysfunction of the mitochondria has been seen in preclinical models of DS as well as primary cell cultures acquired from patients who have been diagnosed with DS. This finding lends credence to the theory that a dysfunction in the mtDNA plays a crucial role in the pathogenesis of DS. A higher amount of mitochondrial ROS production has been associated with deficits in mitochondrial complex I, ATP synthase, ADP/ATP translocator, and adenylate kinase in human skin fibroblasts that have a trisomic karyotype. These impairments were seen in human skin fibroblasts. These defects have been seen in human skin fibroblasts. DS fibroblasts and brain tissue have been shown to include mutations in their mtDNA as well as altered mtDNA repair pathways. iPSCs and neurons produced from DS are more susceptible to the damaging effects of oxidative stress than control cells. People who have DS often have an early onset of immunosenescence as well as a pro-inflammatory profile. This syndrome is defined by a decrease in the activity of natural killer cells, a limitation in the repertoire of T and B cells, telomere erosion in lymphocytes, and an increased risk of autoimmune diseases. In addition, the chance of developing an autoimmune sickness is raised (Trotta et al. 2011; Huggard et al. 2020).
13.1.5.4 Mitochondrial Dysfunction Induced Depression and Social Stress Hollis et al. (2022) reconnoiter the intricate relationship between social stress, neuroinflammation, mitochondrial dysfunction, and the development of depression. It highlights the emerging evidence suggesting that chronic stress, particularly social stress, can lead to neuroinflammatory responses and mitochondrial abnormalities, ultimately contributing to the pathophysiology of depression. The study illustrates the importance of recognizing the risk of depression posed by exposure to persistent social stressors, including social isolation and social defeat. Disruption of neuroplasticity, dysregulation of neurotransmitter systems, and modifications to the hypothalamic-pituitary-adrenal (HPA) axis are only some of the neurobiological changes that are triggered by social stress. These alterations promote the activation of inflammatory processes in the brain and the deregulation of immunological responses. The pathophysiology of depression is heavily influenced by neuroinflammation, which is characterized by the activation of microglia (the brain’s resident immune cells) and the production of pro-inflammatory cytokines and chemokines. Microglia become persistently activated in response to chronic social stress, releasing inflammatory mediators that harm neurons (Bansal and Kuhad 2016). Because of neuroinflammation, ROS are produced, mitochondrial respiration is hampered, and ATP generation decreases. Neuroinflammatory responses are maintained by these mitochondrial abnormalities, which exacerbate the neurotoxic consequences and contribute to depressed symptoms. As it is prementioned that DAMPs are released and inflammatory signaling pathways are activated when mitochondria fail, leading to neuroinflammation. Chronic social stress induces neuroinflammatory responses, which in turn contribute to mitochondrial dysfunction and oxidative stress, ultimately exacerbating depressive symptoms; conversely, neuroinflammation-induced oxidative stress and the release of inflammatory mediators directly impair
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mitochondrial function, establishing a cycle of reciprocal influence. Potential pathways for the prevention and treatment of depression linked with social stress include elucidating the underlying processes and developing tailored therapeutic strategies aiming at restoring mitochondrial function and modifying neuroinflammatory responses (Rezin et al. 2009).
13.1.5.5 How this Problem Can Be Overcome The attainment of effective medication transport into the brain is a significant problem in the pharmacologic treatment of neurodegenerative illnesses. A treatment administered intravenously must first break through the blood-brain barrier before it can reach the brain. This barrier is made up of endothelial cells, which line the tiny blood vessels that make up the brain. The blood-brain barrier has tight connections between neighboring cells to maintain very low permeability to blood molecules, protecting the brain from potentially harmful compounds. As a result, the blood- brain barrier significantly slows the delivery of intravenous medicines to the brain. In the hunt for treatments for neurodegenerative disorders, this constraint has often been disregarded. Further complicating small molecule passage through the blood- brain barrier is the P-glycoprotein, an active efflux mechanism of brain capillaries. Therefore, there will be yet another roadblock in the way of P-glycoprotein substrate medications making it to the brain (Pardridge 2020). The malfunctioning of the mitochondria is improved by biogenesis. It is circumvented by increased glucose absorption as well as glycolysis. It’s possible that these activities may be sped up by the neuronal absorption of very small substances that activate endogenous genes or directly up-regulate pathways. It is important for small molecules to simulate the blood-brain barrier transporter substrates. It’s possible that transcriptional activation from endogenous genes is not necessary for exogenous genes to boost glucagon-like peptide-1 receptor agonist compounds (GLP-1RAs), Hypoxia-inducible factor 1 (HIF-1), and Peroxisome proliferator- activated receptor-gamma coactivator 1 (PGC-1) expression in neurons. HIF-1 may be responsible for the upregulation of glucose absorption and glycolysis that is caused by GLP-1RAs. ATP production is increased when PGC-1 is responsible for mitochondrial biogenesis (Pardridge 2020). Current research into AD is focusing on anti-inflammatory polyphenols. This medication suppresses the generation of cytokines as well as the TLR4/NF-κB/ signal transducer and activator of the transcription signaling cascade in preclinical models of AD. This results in a reduction in the activation of microglia. Another well-known polyphenol is known as epigallocatechin-3-gallate (Capiralla et al. 2012). Immunotherapy has shown promise as a potential treatment for PD. These strategies minimize the amount of alpha-synuclein that is accumulated inside of cells as well as the amount that is transmitted between cells. Patients with PD who use anti- inflammatory drugs and immunosuppressants experience a decrease in the production of pro-inflammatory cytokines, a restoration of lysosome function, and an acceleration of the clearance of beta-synuclein from their systems. These benefits are brought about by the combination of the two classes of drugs. There is some
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evidence that therapy with PD may also target T cells that are implicated in pathogenesis. Possible treatments for PD include preventing the development of TH17 cells, which are involved in the death of dopaminergic neurons or the production of the inflammatory cytokine IL17 (Savitt and Jankovic 2019; Prots and Winner 2019). Moreover, we need to digout more possible therapeutic strategies to overcome the neurodegenerative disorders.
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Molecular and Cellular Mechanism of Pathogen Invasion into the Central Nervous System: Meningitis
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Priyanka Singh, Komal Gupta, Manu Sharma, and Shobhit Kumar
Abstract
Meningitis, a deadly ailment that affects the central nervous system (CNS), involves the inflammation of the brain and spinal cord’s protective membrane, known as meninges. This condition can arise due to infections caused by bacteria, viruses, or fungi. Among the bacterial culprits, Listeria monocytogenes, Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, and H. influenzae type b (Hib) have been identified as potential causes of bacterial meningitis. While fungal-induced meningitis is relatively are, cryptococcal meningitis has been distinguished as a notable exception. Research elucidates that the majority of viral meningitis cases worldwide are attributed to enteroviruses (EVs). In this chapter, we explore molecular and cellular concepts that underlie the mechanisms of pathogen invasion into the CNS. This further encompasses the structural elements of the CNS compartments, which affect the entry of pathogens. Additionally, we present the recent findings regarding the pathways exploited by pathogens to facilitate CNS infections. Thus, this chapter serves to offer valuable insights into the prevalence, incidence, and management of meningitis in both developed and developing nations. By understanding the fundaP. Singh (*) Department of Pharmaceutics, Galgotias College of Pharmacy, Greater Noida, India Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan, India K. Gupta Department of Pharmaceutics, Galgotias College of Pharmacy, Greater Noida, India M. Sharma Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan, India S. Kumar Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_14
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mental aspects of pathogen invasion and CNS interactions, healthcare professionals and researchers can strive to improve prevention strategies and therapeutic interventions for this critical neurological disorder. Keywords
Meningitis · Central nervous system · Bacterial meningitis · Fungal-induced meningitis
14.1 Introduction Neuroinfectious disorders represent some of the most lethal infections, with mortality rates approaching 100%, contingent on factors such as the infecting agent, the age of the host, and their immunological status. Meningitis, a prominent neuroinfectious condition, affects over 1.2 million people globally each year, leading to an estimated 120,000 fatalities (Mazamay et al. 2021). These infections encompass a vast array of viral, bacterial, and fungal organisms capable of causing meningeal or parenchymal illnesses. The primary hallmark of meningitis is inflammation within the cerebrospinal fluid (CSF) chambers, resulting from an infection of the meninges (Thigpen et al. 2011). Pathogens invading the brain parenchyma can infect multiple types of cells, leading to inflammation, excitotoxicity, neuronal network malfunction, localized damage, and cell death (Deigendesch et al. 2018). Incidence rates of neuroinfectious disorders range from 3 to 5 cases per 100,000 individuals annually, with death rates reaching as high as 26% (Nathan and Scheld 2000). Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococci, and Listeria monocytogenes are the most commonly implicated etiological agents (Davis et al. 2008). A few clinical symptoms of bacterial CNS infection include meningitis, meningoencephalitis, and localized CNS disorders (Hongo et al. 2022). In addition to bacterial infections, the CNS can also be targeted by various neurotropic viruses, such as herpes simplex viruses, as well as emerging viruses, examples include the henipaviruses, chikungunya virus, and rabies virus (Abdullahi et al. 2020). The most common symptoms of meningitis involve a stiff neck, a high temperature, sensitivity to light, confusion, headaches, and vomiting (Young and Thomas 2018). Alarmingly, within 48 h of the first symptom onset, 8–15% of people affected individuals die, even with timely diagnosis and treatment. If left untreated, meningococcal meningitis carries a 50% fatality rate, and among survivors, 10–20% may develop brain damage, hearing loss, or a learning disability (WHO 2023). The natural entry points for pathogens into the CNS include the skin, mucosal surfaces of the respiratory, digestive, and urinary systems, as well as the nasopharynx. Once pathogens overcome these mucosal or dermal barriers, they can access the CNS either directly via peripheral neurons or indirectly through channels requiring hematogenous dispersion. The concept of the blood-brain barrier (BBB) emerged from the work of Battelli and Stern (1912), who observed that systemically administered dyes failed to penetrate the developing mammalian brain. Since then,
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studies have demonstrated that the BBB blocks the passage of immune cells into the CNS (Wilson et al. 2010; Barker and Widner 2004). However, certain neurotropic infections evade the BBB, which typically guards the CNS against infectious illnesses agents, through transneuronal pathogen invasion. Conversely, other infections may penetrate the BBB to enter the CNS parenchyma through hematogenous pathways (Cain et al. 2019). The mechanism underlying the entry of neurotropic infections into the CNS are currently topics of ongoing research and will be comprehensively covered in this review.
14.2 Barriers of the Central Nervous System The Central Nervous System (CNS) is surrounded and protected by several physical barriers, including the meninges and CSF as well as the vertebrae and cranium. The three layers that make up the meninges are the pia mater, the dura mater, and the arachnoid mater. The CSF plays a vital role in maintaining the CNS’s health by controlling ion composition, chemical stability, and providing mechanical support. It circulates through the brain’s ventricles and eventually reaches the subarachnoid space (SAS) before being absorbed into the circulation. Additionally, CSF leaves the nasal mucosa via the lymphatics of the cribriform plate (Walter et al. 2006; Brinker et al. 1997; Mollanji et al. 2001). Homeostatic systems that control ion concentration of interstitial fluid that surrounds neurons in parenchyma are necessary for intricate brain activities (Abbott 2013). This equilibrium is maintained by two cellular barriers: the brain-CSF barrier (BCSFB) and the BBB, which segregate the CNS from the remaining body. These barriers provide protection to the brain from quick changes in the biochemistry of blood while allowing nourishment delivery and metabolite removal. Importantly, these defenses also prevent blood-borne pathogens from invading CNS (Engelhardt and Sorokin 2009).
14.2.1 Blood-Brain Barrier The cerebral capillary endothelium and the epithelium of the choroid plexus are responsible for creating the blood-cerebrospinal fluid barrier and the BBB, respectively. The BBB is composed of microglia, neurons, and immune cells from the periphery, cells lining cerebral microvessels, astrocytes, and the basement membrane (together known as neurovascular unit) Fig. 14.1 (Abbott et al. 2010). Pericytes play a crucial role in maintaining a continuous barrier membrane. The close connections between the cerebral artery endothelial cells (ECs) and the choroid plexus epithelium prevent substances from easily traveling through the BBB (Kadry et al. 2020). The BBB is primarily composed of adherens junctions and tight junctions (TJs) at the interendothelial cleft, which significantly limits the paracellular permeability across the BBB. These junctions prevent a wide range of substances from passing through (Lochhead et al. 2020). Additionally, the lack of fenestrations in the plasma membranes of BBB’s ECs and their relatively low
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Fig. 14.1 Blood-brain barrier architecture: the BBB consists of unbroken endothelial cells (ECs) that are interconnected through TJs. This, along with pericytes, astrocytes, microglia, constitutes a protective barrier
number of pinocytotic vesicles further restrict transcellular flux (Engelhardt and Sorokin 2009). For microbial infections, understanding the routes of entry, whether transcellular or paracellular, into the CNS is crucial (Geier et al. 2013; Uchida et al. 2011; Shawahna et al. 2011). These entry routes can have significant implications for how infections and other substances affect the CNS.
14.2.2 The Blood Cerebrospinal Fluid Barrier (BCSFB) BCSFB is created through the presence of TJs between two types of cells: (1) epithelial cells are present on the choroid plexus in the lateral, third, and fourth ventricles of the brain, (2) ECs are found in the SAS’s veins and venules. The presence of tight connections between the epithelial cells of the arachnoid mater is responsible for creating a separation between the SAS and the permeable, fenestrated blood vessels of the dura maters (Bulat and Klarica 2011). The choroid plexus is one of the sites of BCSFB. It has a significant vascular surface area and serves as the primary point of contact between fenestrated blood vessels and CSF. The BCSFB’s main functions are CNS protection and homeostasis maintenance. It achieves this by preventing the entry of numerous blood-borne substances into the CNS. The choroidal epithelial cells of BCSFB are responsible to produce CSF within the choroid plexus and transporting it into the ventricular system of brain. Additionally, the electrical resistance of the TJs between these epithelial cells is lower compared to the tight connections in the ECs of the BBB (Redzic 2011). As a result, the choroid plexus of BCSFB could be more susceptible to microbial penetration through paracellular mechanisms (Johanson 2017) (Fig. 14.2).
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Fig. 14.2 Blood-cerebrospinal fluid barrier architecture: BCSFB consists of the choroid plexus epithelium which is situated among the choroid plexus capillaries and the CSF. When substances pass the choroid plexus epithelium. Then, they gain entry to the CSF, wherein they have the potential to diffuse into the brain tissue
14.3 Bacterial Meningitis Bacterial meningitis is the inflammation of the meninges. Meninges are the protective coverings that surround the brain and spinal cord. Among the bacterial culprits, Listeria monocytogenes, Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, and H. influenzae type b (Hib) have been identified as potential causes of bacterial meningitis (Thigpen et al. 2011). The prevalence of bacterial meningitis and the presence of the causative agent vary depending on the age of children and the geographical distribution. Bacterial agents show high affinities for children of different age groups. Gramme negative-2 bacteria, including Escherichia coli, K. pneumoniae, Group B Streptococci, and Listeria monocytogenes, are responsible for causing meningitis in neonates and Pneumococcal meningitis occurs more frequently in children under the age of 5 years (Runde et al. 2023). Bacterial meningitis is a prominent infectious disease that kill people all over the world and also contributes to various neurological disabilities among survivors. Neurological complications resulting from bacterial meningitis are attributed to one or more of the following factors: (1) vasculitis, (2) brain edema, and (3) inflammatory exudates within the SAS (often most pronounced over basal cisterns) due to meningeal inflammation, leading to impaired CSF resorption (Ramgopal et al. 2019). Inflammation of the blood vessels traversing the SAS (arthritis, phlebitis) is common in bacterial meningitis and it can be particularly severe when S. pneumonia is the causative agent. This vasculitis can cause luminal narrowing or thrombus formation within the blood vessels, potentially leading to ischemia and sometimes
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infarction of the cerebral cortex. As a result, individuals may experience impaired consciousness, focal neurologic deficits, and/or seizures (Fuentes-Antrás et al. 2019).
14.3.1 Mechanism of Bacterial Meningitis Bacteria can cross BCSFB and BBB and enter CNS through two primary pathways: either through paracellular entrance or through contaminated leukocytes of peripheral circulation (the “Trojan horse” mechanism). Transcellular penetration takes place when bacteria adhere to endothelial or epithelial cells, facilitating their passage through these cell layers (Scheld et al. 2002). Alternately, bacteria can enter the CNS paracellularly after breaking the tight junction between cells that make up the BBB and/or BCSFB, causing an increase in permeability. Bacteria may use more than one of these mechanisms to enter into the CNS (Doran et al. 2016). Their ability to invade depends on the presence of pIgR on the surface of epithelial cells, which is responsible for facilitating transcellular antibody transfer (Du et al. 2006). By binding to pIgR, bacterial choline-binding protein A (CbpA) is thought to form a channel through which bacteria enter the intravascular space. Furthermore, bacterial hyaluronidase breaks down hyaluronate, leading to further damage to the protective barriers (Wang et al. 2016). Research revealed that the survival of intravascular pathogens relies on the existence of cell membrane polysaccharides that provide protection from phagocytosis (Nau and Brück 2002). The development of meningitis is not solely dependent on severe bacteraemia since the intravascular space is effectively separated from the CNS through both BBB and BCSFB (Tuomanen 1996). Bacterial invasion and transmigration lead to the activation of the plateletactivating factor receptor on the surface of ECs. This receptor binds to bacterial wall phosphorylcholine, triggering a response (Wang et al. 2016). The interaction between the EC, PAF receptor, and the bacterium results in the formation of a vacuole that enables the translocation of the pathogen to the SAS (Ring et al. 1998). The proliferation of bacteria in the CSF induces alterations in the barrier’s permeability. The disruption of the highly efficient blood-CSF barrier leads to the entry of serum proteins, such as immunoglobulin and complement. Furthermore, the presence of bacteria in the CSF generates chemotactic activity and/or arachidonic acid metabolites (Kornelisse et al. 1995). The absence of natural defense mechanisms in the CSF, such as polymorphonuclear leukocytes (PMNL), the complement system, and immunoglobulins allows pathogens to proliferate unrestrictedly (Stahel et al. 1996). Upon encountering bacteria, PMNL becomes activated and undergoes a complex process of migration from the intravascular space to the SAS. Throughout this process, there is a sequential activation of receptors and adhesion ligands on both vascular ECs and PMNL. This activation results in binding, subsequent activation, persistent adhesion, and ultimately migration of PMNL to the target site (Kubes and Ward 2000). P-, E-, and L-selectins are responsible for the initiation of the transfer process. Afterward, activated PMNL binds to intercellular adhesion molecule 1 (ICAM-1) at the vascular endothelial cell by the macrophage antigen 1 (Mac1) integrin. This interaction leads to sustained adhesion and triggers the PMNL’s
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migration to the SAS through a chemotactic gradient mechanism. The bacterial wall releases peptidoglycan and lipoteichoic acid and activates membrane CD14 (mCD14) receptor and the toll-like receptor 2 (TLR2) in peripheral blood-derived PMNL. This activation subsequently induces the relocation of the nuclear factor-κB (NF-κB) from the cytoplasm to the nucleus (Takeda and Akira 2005). The main activator of gene transcription is NF-B. Tumor necrosis factor alfa, interleukin-beta (IL-1β) and interleukin-6 are examples of inflammatory mediators that are produced and released by NF-κB (Gerber and Nau 2010). IL-1β and TNF-α play a major role in stimulating the upregulation of adhesion molecule that facilitates the translocation of PMNL from blood vessels to SAS (Koedel et al. 2002). The morphological and functional alterations in PMNL that take place intravascularly result in the proliferation of EC. Bacteria and PMNL along with released proteins translocate to the SAS, contributing to the formation of the inflammatory infiltrate (Rofes et al. 2022). As a consequence of these alterations, there is vascular obstruction and evident morphological signs of an inflammatory reaction within the SAS, reaching its peak at 48 h. If damaging processes are stopped, adhesion formation, arachnoid fibrosis, and vascular recanalization take place during the following few days (Chávez- Bueno and McCracken 2005). Vascular occlusion causing impaired cerebral tissue perfusion results in disruptions to the homeostasis of the CNS immune system, which is composed of mainly microglial cells and astrocytes. Indirect evidence indicates that Streptococcus pneumoniae enters CSF through the meningeal vessels while Hemophilus influenzae enters through the choroid plexus (Rzaska et al. 2017).
14.3.2 Neisseria Meningitidis Neisseria meningitidis is an example of a gram-negative bacteria. This is the primary source of bacterial meningitis and sepsis in humans. N. meningitidis is present in nasopharynx of adults asymptomatically (Rouphael and Stephens 2012). Meningococcal infection usually starts within 1–14 days after coming in contact with bacteria. Neisseria meningitidis interacts with human endothelial and epithelial cells. Several microbial components and proteins, including type IV pili, PilC, N. meningitidis adhesin A (NadA), and Opa and Opc proteins, are involved in this interaction. The invasion of Human brain microvessel endothelial cells (HBMEC)s by unencapsulated N. meningitidis occurs when Opc binds to fibronectin, effectively anchoring the bacteria to the integrin α5β1 receptor located on the surface of HBMECs. The pili of N. meningitidis attach to CD46 on HBMECs (Johansson et al. 2003). Their lipooligosaccharides are known to cause an enormous amount of bacteraemia and subsequent penetration into the CNS (Plant et al. 2006). By releasing local inflammatory cytokines and nitric oxide, the BBB is disrupted, resulting in edema, induction of apoptosis, and formation of clots in vessels. When looking through a microscope, a remarkable and intense infiltration of meninges, blood vessels, Virchow-Robin spaces, and perivascular parenchyma with both polymorphonuclear and mononuclear inflammatory cells is observed (Stephens et al. 2007). As a result, the thickening of blood vessels causes thrombosis, blockage, localized
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impairments, and cerebral infarction. A concentration of pus is found at the base of the brain and on the outer surface of the cerebral cortex. Intracranial pressure increases as a result of exudates blocking CSF channels (Memish and Alrajhi 2002).
14.3.3 Escherichia coli Escherichia coli migrates from the top compartment to the bottom compartment without raising cellular permeability in an HBMEC Transwell model thereby supporting penetration of transcellular mechanism. The potential location of entrance into the CSF was investigated and determined using neonatal rat models of Escherichia coli meningitis. Escherichia coli attaches to the luminal surfaces of vascular ECs, choroid epithelial cells, and ependymal cells that surround the brain ventricles, according to research (Parkkinen et al. 1988). The entry of Escherichia coli K1 into the CSF is achieved by choroid plexus and then it reaches the CSF and finally, it adheres to the meninges (Zelmer et al. 2008). Another scientist found that Escherichia coli was localized in the perivascular regions of the SAS instead of the choroid plexus in the brain of an experimental rat (5 days old). Numerous Escherichia coli proteins play an important role in adhering to and invading HBMECs (human brain microvascular ECs). When Escherichia coli attaches to HBMECs, it triggers rearrangements of host cytoskeletal.. Then, it causes actin condensation beneath the adherent bacteria (Kim et al. 1992). This process involves the CNF-1-mediated recruitment of focal adhesion kinase and the cytoskeletal protein paxillin to the 67-kDa laminin receptor. Subsequently, these recruited proteins form the clusters that colocalize with adherent Escherichia coli. When Escherichia coli interacts with HBMECs, it leads to the tyrosine phosphorylation of focal adhesion kinase and paxillin. Focal kinase activity and autophosphorylation site (tyrosine 397) were found to be crucial to invade HBMECs by Escherichia coli (Reddy et al. 2000).
14.3.4 Streptococcus pneumoniae Researchers recently investigated the spatiotemporal events of CNS invasion in the experimental model of pneumococcal meningitis (BALB/c) (Iovino et al. 2013). S. pneumoniae can pass the BBB when it is alive (Thomas et al. 2011). After the 1 h infection. S. pneumoniae showed attaching to SAS blood vessels, and it organized into clusters surrounding the endothelium. Interestingly, pneumococci were only detectable within the choroid plexus after 8 h post-infection. So, it indicates that this location is not the initial entry point to the CSF., the main adhesion protein of S. pneumoniae pilus-1 is RrgA, which showed a strong binding affinity for the polymeric immunoglobulin receptor and platelet-associated cell adhesion molecule (PECAM)-1 on the endothelial cell. The bacterial choline-binding protein simply binds to pIgR (Iovino et al. 2017). During severe infections, S. pneumoniae can potentially reach the brain parenchyma by damaging endothelial cell membranes or TJs through the action of pneumococcal pneumolysin (Bogaert et al. 2004).
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14.3.5 Haemophillus influenzae Meningitis Histopathologic lesions in H. influenzae meningitis were first observed at the choroid plexus in experimentally infected rhesus macaques (Morsli et al. 2021). After intranasal injection, Haemophillus influenzae was obtained from the CSF of the lateral cerebral ventricle. This was accompanied by mild choroid plexitis and intravascular inflammatory infiltrate. The receptor of platelet-activating factor on ECs of brain microvascular can interact with H. influenzae pili (Orihuela et al. 2009).
14.3.6 Listeria monocytogenes In comparison to other neuroinvasive bacteria, the intracellular bacterium Listeria monocytogenes is more effective in invading CNS (Drevets et al. 2004). Following intake of contaminated food, L. monocytogenes spreads from the gastrointestinal system through the bloodstream. It enters the parenchyma of CNS by numerous different mechanisms, that involve meningeal endothelium invasion, passage through infected macrophages to the other side of BBB, followed by migration of cranial nerve axons (Vásquez Alva et al. 2020). Additionally, internalin InlF and its cell surface receptor vimentin are involved in L. monocytogenes’ invasion of the brain, which improves brain ECs interaction with it (Magiar et al. 2022).
14.4 Viral Meningitis Meningitis occasionally co-occurs with common viral or bacterial diseases like influenza, chickenpox, or streptococcus pharyngitis and manifests as an intense headache and meningeal irritation without CSF pleocytosis, while viral meningitis is characterized by normal glucose levels, CSF pleocytosis, elevated protein content, fever, and meningeal irritation symptoms such headache, vomiting, and nuchal stiffness (Nagafuchi et al. 2006). The most frequent condition that affects the CNS is viral meningitis. Babies and young adults are mostly affected by viral meningitis. In many countries today, viral meningitis surpasses bacterial meningitis by a ratio of more than 25:1 (Davis 2008). Enteroviruses (EVs) are member of Picornaviridae family. They are responsible for causing meningitis in 90% of cases (Le Govic et al. 2022). Patients with aseptic meningitis are most usually found to have EV-A71, EV-D68 and Coxsackievirus B. Human parechoviruses (HPeVs) are another family of Picornaviridae that frequently cause meningitis. EVs can penetrate the epithelial cells of the upper respiratory tract and intestine, which then move to blood and CNS via infected immune cells (Kohil et al. 2021). EV meningitis typically manifests as a mild, self-limiting illness. The other common cause of viral meningitis is the Herpesviridae virus family member. Epstein-Barr virus (EBV), herpes simplex virus 2 are also known to cause meningitis, HSV-2 is the most common cause. Meningitis may arise from an HSV-2 original infection or reactivation (Wright et al. 2019). The mumps virus is
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also responsible for the viral meningitis. Infected people with mumps virus have symptoms like parotitis and hearing loss (Mallewa et al. 2013).
14.4.1 Mechanism of Viral Meningitis There are essentially two major ways that viruses enter the CNS. The first entry point of CNS invasion is the blood supply. Human EVs can easily cross mucosal epithelial barriers to infect oropharyngeal or small bowel lymphoid organs. Inhaled viruses like measles and mumps and ingested viruses like these can also do this (Jubelt and Lipton 2014; Griffin 2014). After an insect attack, Langerhans cells take up arboviruses that enter the epidermis and go to the draining lymph node (Wu et al. 2000). Viruses frequently shed into the bloodstream after entering secondary lymphoid tissues, leading to systemic infection. The blood-brain and CSF barriers form a complex barrier network that shields the sensitive CNS parenchyma from dangerous chemicals in the blood (Swanson and McGavern 2015). However, viruses have developed several strategies to get through these barriers (McGavern and Kang 2011). Few can enter vascular ECs directly, allowing them to penetrate BBB and enter into CNS directly (Verma et al. 2009; Coyne et al. 2007). Additionally, the BBB does not entirely protect CNS, including the circumventricular organs and choroid plexus, which act as entry routes for a number of viruses (Van Den Pol et al. 1999). Another method of delivering viruses into CNS through the blood supply uses Trojan horses (Clay et al. 2007). Lastly, systemic viral infection causes BBB failure brought on by inflammation (Arsénio-Nunes et al. 1975; Eugenin et al. 2006), allowing viruses to literally invade the CNS. Other viruses enter and spread through peripheral nerves, which is a secondary and important pathway for CNS invasion. Both the poliovirus and the rabies virus employ peripheral motor neurons to enter CNS, even though poliovirus initially infects mucosal epithelial cells after ingestion and after an animal bite, the rabies virus initially attacks myocytes (Racaniello 2006; Nadal et al. 2022). Keratinocytes are initially infected by herpes simplex virus (HSV)-1, which then spreads to nearby neurons that are sensory. Furthermore, HSV-1 penetrates CNS through olfactory sensory neurons whose dendrites are in close proximity through the nasal passage (Mori et al. 2005). Additionally, it has been proposed that olfactory neurons are a common pathway for rabies, influenza, and Nipah viruses to enter the CNS (Munster et al. 2012; Schrauwen et al. 2012). Viral tropism and the subsequent immune response work together once viruses have entered the CNS to shape the disease. Meningitis is frequently brought on by viruses that persist in the ventricular lining or meningeal cells (Nathanson 2008).
14.4.2 Epidemiology The majority of EVs are identified as the viral etiology. Frequently, the similar serotype enterovirus circulates simultaneously in many locations. The second main
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reason is herpes simplex type 2. Since viral meningitis is typically not an illness that needs to be reported, the real incidence is unclear. The main reasons for viral meningitis are the herpes simplex 2 virus, arboviruses, mumps virus, and EVs. Nowadays, the majority of cases of mumps meningitis occur in nations that do not regularly offer the mumps vaccine. Most cases of HSV-2 meningitis affect young, sexually active people. In temperate areas, EVs predominate in the summer, when viral meningitis is most common (Bale 2011) 1. Enteroviruses: In temperate regions, EVs are common in children and are most prevalent in the summer and autumn. Usually benign, although there can be severe morbidity and mortality in newborns. Those newborns who are immunosuppressed (especially those who have agammaglobulinemia) and also who are infected with the enterovirus 71 epidemic. Meningoencephalitis and myo/pericarditis are the most commonly seen serious effects (Chadwick 2005). 2. Herpes virus: The HSVs are the most prevalent herpesviruses that infect the CNS and most common causes of sporadic encephalitis (acute) amongst adults and children over the age of 6 months. These viruses can lead to infections which involve encephalitis, myelitis, meningitis, and sporadically radiculitis (mostly sacral), but encephalitis is the most severe amongst them all that has a death rate over 70% when left without treatment. Like other types of meningitis, HSV meningitis commonly results in headaches, a stiff neck, and fever in most people. Meningoencephalitis is also associated with the EBV, human herpesvirus 6, cytomegalovirus (CMV), varicella-zoster virus (VZV), and other herpesviruses. Immunocompromised individuals make up the bulk of those who contract these viruses’ CNS infections, and advanced HIV infection has been related to persistent meningoencephalitis caused by CMV in particular. 3. Mumps: Males are more frequently affected than females by the mumps, which are common in nonimmunized communities. 4. West Nile virus: Maximum cases of this mosquito-transmitted infection occur in the late summer in temperate regions. This virus has become prevalent not just in Asia, Europe, and Africa, but also over all of North America. Mortality cases are within the range from 4% to 13%, mostly higher in elderly people, diabetics patient, and people who are immunosuppressed. Fifty percent of people who had encephalitis had a chronic neurological or mental impairment. 5. Japanese B encephalitis: This infection is spread by mosquitoes mainly in Southeast Asia. Pigs are a significant natural host and are more common in rural areas and during the winter. Children and nonimmune adults are the most commonly affected. Mortality rates are 20–30%, with up to 30–% of deaths resulting in long-term neurological impairment. 6. Tick-borne encephalitis: Tick-borne illness predominantly contracted in Europe and Asia; most common in the spring and early summer; causes 1–2% of cases to be deadly, with the Far Eastern form having the greatest fatality rates. Compared to other viral encephalitides, the disease is typically more persistent.
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7. Human immunodeficiency virus (HIV): Develops sporadically during chronic infection and in 5–10% of patients during, right after, or close to a seroconversion illness. Rarely do consequences arise from early HIV infection. Seroconversion illness can also result in a maculopapular rash, fever, myalgia, and lymphadenopathy. HIV-related dementia complex is a chronic infection. 8. Herpes simplex virus: These infect people on occasion. HSV-1 and HSV-2 are more commonly linked to encephalitis and meningitis, respectively. Encephalitis has a 70% mortality rate if left untreated. HSV-2 meningitis may also occur in the absence of clinical genital herpes have written in place of often a localised encephalitis (affecting temporal lobes). Numerous HSV-2 instances are unrelated to genital herpes may lead to Mollaret’s meningitis, a recurring meningitis. 9. Cytomegalovirus (CMV): Mostly in patients with impaired immune systems. Afocal encephalitis may exhibit symptoms similar to those of mononucleosis. This infection may be accompanied by CMV retinitis. 10. Varicella-zoster virus (VZV): Shingles or chickenpox-related uncommon complications are more likely in immunocompromised individuals. Meningitis without vesicles (zoster sine herpete) can occasionally be detected. Elderly people who have recently had zoster may experience a stroke or more diffuse chronic encephalitis (Momméja-Marin et al. 2003).
14.4.3 Pathogenesis There are numerous methods for viral transmission to reach the human host, and there are a number of defense systems in place to stop viral spread. Lymphoid tissue near the infection site frequently experiences local viral replication, which can serve as a reservoir and result in secondary viremia (Shaw and Cohen 1993). Secondary viremia more frequently spreads the CNS virus (Cassady and Whitley 2016). Viral CNS invasion can take place directly through olfactory neurons, through the choroid plexus epithelium, through cerebral capillary ECs that are protected by leukocytes, or by moving down peripheral nerves (Sellner et al. 2010; Cassady and Whitley 2014). This mechanism promotes the proliferation of mononuclear cells, which may at first be polymorphonuclear before becoming mononuclear in some situations. When mononuclear cells present viral antigens, this promotes an immune cell influx that results in cytokine production, increased BBB permeability, and an influx of serum immune globulins. Both humoral and cell-mediated immunity are crucial for the protection of the host and the elimination of the virus from the CNS (Tunkel et al. 2010). Neck stiffness and physical examination findings, which are common meningitis clinical indications indicating nerve root irritation, are caused by this inflammatory process (Brody and Wilkins 1969). The inflammatory reaction can progress and cause cerebral edema, vasculitis, and cell necrosis. The main haematogenic route by which the pathogenic organisms enter the CNS. Viruses typically enter the blood after colonizing the mucosal surfaces throughout the body. They often multiply at extraneural locations before crossing
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the BBB and infecting CNS. The choroid plexus, cerebral microvascular ECs, cerebral capillary ECs, and certain viruses are delivered past the barrier by infected leukocytes are the four main routes by which viruses enter the CNS. The olfactory nerve and peripheral nerves are two pathways via which certain viruses can enter the CNS. The way the virus enters the CNS affects how it spreads once inside the CNS. The immune response is triggered against myelin basic protein as well as the infecting agent in certain viral and mycoplasmal infections, as well as after vaccinations. When the CNS myelin is impacted, acute disseminated encephalomyelitis results from the immune reaction against myelin in the peripheral nerves and nerve roots (Pokorn 2004).
14.4.3.1 Family Picornaviridae Enteroviruses Both the fecal-oral pathway and respiratory secretions can be used to spread EVs (Burrell et al. 2017). Additionally, they can be passed vertically from an infected mother to her unborn child through breastfeeding or placental contact (Méreaux et al. 2017). The virus mostly multiplies in cells of the intestinal mucosa, oropharyngeal epithelium, and nasopharyngeal epithelium when it enters the body (Majer et al. 2020). It often takes entry to body through lower gastrointestinal tract, travels to the Peyer’s patches, and multiplies, and finally exits by the oral-fecal pathway. It binds to this on the surface of the enterocytes to the particular receptor (Rotbart 2000). Additionally, a virus might infect immune cells before entering the bloodstream and at other locations cause secondary infections, like heart and CNS (Palacios and Oberste 2005). The spread of the virus causes a variety of consequences, including encephalitis and meningitis (de Crom et al. 2016). Meningitis and other neurological conditions are known to be brought on Enterovirus B species member, Coxsackievirus B (Berger et al. 2006). Infected mononuclear cells (Mac-3), which have the capacity to cross blood-brain barrier and infiltrate epithelium of choroid plexus, can carry coxsackievirus to CNS (Huang and Shih 2015). Extracellular signal-regulated kinases are activated in the following manner, which encourages viral multiplication inside leukocytes, particularly T cells (Opavsky et al. 2002). Human Parechovirus (HPeV) HPeV can be spread by saliva and respiratory secretions, mostly causing respiratory infections (Aizawa and Saitoh 2015). The HPeV strain most frequently linked to viral meningitis is HPeV-3 (Wolthers et al. 2008). Furthermore, HPeV-3 has been found to employ a distinct RBS-receptor binding site than other serotypes of HPeV, which use the arginine-glycine-glutamic acid sequence motif at the carboxyl terminus of VP (capsid protein) (Stanway et al. 2000).
14.4.3.2 Family Herpesviridae Human herpesvirus types 1 and 2 (HSV-1 and HSV-2), VZV, and EBV are main Herpesviridae members that can cause meningitis. Each of these viruses has the
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capacity to induce meningitis and leave neurons with a dormant infection that could become active in the future (Spear and Longnecker 2003). The three identified cellular receptors for HSV are herpesvirus entry mediator (HVEM), immunoglobulin superfamily members, and heparan sulfate generated by certain isoforms of 3-O-sulfotransferases (Johannessen and Burns 2012). HVEM is present on the surfaces of many different types of cells, that include neurons and epithelial cells. Therefore, it is suggested that entry of the virus through a receptor is what causes meningitis. EBV pathogenesis is started with cells of oropharyngeal epithelial become infected. It enters lymphoid tissue and spreads infection to B cells of lymphoid. The population of infected B cells may have lytic or dormant virus. Latent membrane proteins and Epstein-Barr nuclear antigens are primarily expressed by the virus at this stage (Akkoc et al. 2016). By infecting the blood vessels of cells of endothelial in the brain, the virus may result in latent infection. When under stress, certain chemokines and cytokines, such as IL-1, TNF-, IL-12, and IL-18, are expressed more frequently, which causes an inflammatory reaction (Koyuncu et al. 2013).
14.4.3.3 Family Orthomyxoviridae The olfactory system and many cranial nerves are two possible entry points for the influenza virus into the CNS (Yamada et al. 2012; Siegers et al. 2019). A virus typically attaches to the 2,6- and 2,3-linked sialic acids that are found on the epithelial cells of lower and upper respiratory tract (Imai and Kawaoka 2012) as well as in the cerebral cortex and brainstem neurons (Yamada et al. 2012; Kim et al. 2013). These elements, when combined, help explain how the influenza virus spreads to the CNS, to lead to a variety of neurological conditions, including meningitis.
14.4.4 Arboviruses These can enter the body by skin bites from infected arthropods, causing local lymph node infection, viremia, transmission to CNS, which can cause meningitis (Irani 2008).
14.4.4.1 Pathophysiology The EVs gastrointestinal tract, for arboviruses the subcutaneous tissue after a mosquito or tick bite, the mumps respiratory tract, and the infection of vaginal skin for HSV2 virus are the main foci of infection connected to the virus’s entry point. Viremia can spread from the place of origin to distant locations via infecting neighboring peripheral nerves in the skin, as in the case of an infection with the HSV-2 virus, or via lymphatic transfer of progeny viruses from the GI tract, subcutaneous tissue, or respiratory tract to blood (Jubelt and Lipton 2014). The virus most frequently enters the meninges through viremia. There are numerous significant host barriers that must be broken down for a viremia to develop meningitis. Viral circulation in blood is effectively filtered by the reticuloendothelial system (RES). Immune responses on the cellular and humoral levels effectively end viremia. Days after the
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first infection, the manufacture of antibodies, often of the IgM type, starts. The humoral immune response can get hampered by immunosuppression. The BBB stands as the virus’s last barrier to entry into the CNS. This intricate barrier between cerebral ECs keeps numerous circulating chemicals and infectious pathogens out of the brain. Uncertainty surrounds the real process by which the meningitis virus enters the CSF (Leveque et al. 2011). Because of the infection of other organs, the majority of viral infections are therefore asymptomatic or only very weakly infectious. Few neurotropic viruses have antiviral treatments; therefore, the immune system of the host is primarily in charge of removing meninges infection. Unfortunately, because the brain and meninges have poor host defenses, clearance of viral matter from infection of CNS is little effective compared to infections in any other part of the body (Mohseni and Wilde 2012). For instance, CSF has far lower antibody titers than serum, has fewer lymphocytes than normal CSF, and does not have a lymphatic system in the brain. However, during an active viral infection, immune monocytes can pass through the meninges, CNS monocytes can release cytokines such gamma interferon, and neutralizing antibodies can enter the CSF, generally to kill the virus. Since only the meninges are impacted by the virus that causes viral meningitis, the CNS infection normally clears itself within 1–2 weeks with little to no neurological aftereffects (Nowak et al. 2003). Up to 80% of viral meningitis can be brought on by enterovirus infections. The A, B, C, and D species of human enterovirus are currently separated from the group of EVs, a group of approximately 77 serotypes. According to Rosenberg and Galen (2017), these tiny (30 nm in diameter) virions may easily survive in both water and sewage (Rosenberg and Galen 2017). Fecal contamination, such as using the loo without washing one’s hands, is the main way that EVs are spread from person to person. EVs can persist in the stool for weeks (Steiner and Benninger 2013).
14.5 Fungal Meningitis A dangerous condition known as fungus meningitis affects mostly immunocompromised people and is brought on by a fungus infection of the CNS. Without adequate treatment, fungus meningitis frequently results in death, and even when antifungal medication is used, the mortality rate is still too high (Liu et al. 2012). Fungi are saprophytic (eukaryotes) creatures that possess membrane-bound nuclei that devour organic materials, in contrast to bacteria. In immunocompromised hosts, the majority of CNS fungal infections are opportunistic and spread by blood. However, reports of immune-competent people serving as potential hosts for such illnesses are growing (Kwon-Chung and Bennett 1984). Direct inoculation of fungal spores, such as during surgery or trauma, is a common source of fungus infections. Molds (filamentous fungus), dimorphic fungi, and yeasts are among the main medical fungi that enter the CNS. Numerous common yeast species, including Candida spp. and Cryptococcus neoformans, which exhibit high neurotropism, are able to spread disease throughout the CNS. Third category of common neurotropic molds includes phaeohyphomycetes (dark molds), which includes Cladophialophora
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bantiana, Exophiala dermatitidis, and Rhinocladiella mackenziei. The pathogenesis of CNS lesions is significantly influenced by the shape of the fungus. Dimorphic fungi and species of Cryptococcus and Candida predominantly cause meningitis or meningoencephalitis when they proliferate In Vivo as budding yeasts (Mendonça et al. 2021).
14.5.1 Etiology 1. Cryptococcosis: Asymptomatic or symptomatic lung infections, as well as subacute or chronic meningitis, can all be brought on by inhaling airborne Cryptococcus neoformans spores. The signs include hearing loss, face numbness, double vision, and visual impairment, as well as headaches, nausea, papilledema, seizures, and altered sensorium. 2. Coccidioides immitis: The virulent dimorphic fungus Coccidioides immitis causes coccidioidomycosis, which is characterized by severe meningeal inflammation, exudate buildup, opacification of the leptomeninges, as well as the basal cisterns’ sulci being destroyed by caseous granulomatous nodules (Sharma 2010; Sharma and Sharma 2018). 3. Candidiasis: Whether contracted through community contact or a nosocomial infection, candidiasis is a prevalent cerebral mycosis. Hematogenous spreads to CNS typically originate in oropharyngo-esophageal areas and frequently result in meningitis and, less frequently, cerebral abscess. 4. Histoplasma capsulatum: Another soil contaminant is histoplasma capsulatum. Single or multiple cerebral granulomas, meningitis, and CNS histoplasmosis occur in 20% of cases with systemic histoplasmosis. Histoplasmosis typically causes the subarachnoid gaps to disappear along with meningeal inflammation that stimulates fibroblastic proliferation (McCarthy et al. 2017). 5. Aspergillus and zygomycetes: The upper respiratory tract and the paranasal sinuses are initially colonized by Aspergillus and zygomycetes. Then, these creatures began to directly extend across the cartilage, blood vessels, bones, tissues, and nerves. Local tissue and vascular invasion come next. They can also cause meningitis, thrombophlebitis, arteritis, thrombophlebitis abscesses, and cerebral granulomas. Cerebral infarction is caused by vascular invasion (Gonzalez-Lara and Ostrosky-Zeichner 2021).
14.6 Invasion of the CNS and Interaction with the BBB by Fungi It is still unclear how FIs-CNS pathophysiology works. The BBB is broken down in order to reach the infection to CNS. Pathogen may penetrate the brain parenchyma before circulating into blood, when pathogen penetrate then they must first be blocked in the brain microvasculature, which involves blood-brain barrier (BBB) transmigration. Pathogens can cross the BBB via three distinct
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mechanisms: paracellular migration, transcellular migration, and the Trojan horse mechanism (Koutsouras et al. 2017). The most well-understood mechanisms are those of Candida and Cryptococcus. Both direct and indirect methods can be used by C. neoformans mechanically arrested in the brain vasculature to cross BBB (Góralska et al. 2018). Indirect methods require transfer inside the phagocytes as a mechanism of Trojan Horse, whereas direct mechanisms entail BBB crossing by endothelial cell transcytosis (Colombo and Rodrigues 2015; Casadevall 2010). According to recent research, C. neoformans uses a transcellular pathway in BMECs that necessitates the activation of protein kinase C-alpha. The CPS1 gene is necessary for C. neoformans so as to adhere to human BMECs’ CD44 protein present on the surface. The Isc1 gene encodes an inositol hydrolyzing enzyme, which regulates the entry of pathogens into the brain. Recently, Huang et al. (2012) established that the lipid raft-endocytic pathway is the pathway by which Cryptococcus neoformans invades human BMECs. Fibronectin, laminin, and vitronectin promote C. albicans adhesion to the extracellular matrix. According to research by Liu et al. (2011), the fungi Als3 and Ssa1 make it easier for C. albicans to invade brain ECs. The fungus increases endothelial transcytosis after binding of Als3 to the heat shock protein of gp96, which is solely presented on the brain endothelium (Shi and Mody 2016). A peripherally located phagocyte becomes infected to begin the Trojan Horse route. When the virus has been internalized, the phagocyte may be manipulated to encourage brain migration. When the phagocyte that is infected enters the brain, it penetrates BBB either paracellularly or transcellularly by attaching to cerebral capillaries luminal side (Santiago-Tirado and Doering 2017). Reduced immunity causes the BBB to become more permeable, which makes it easier for fungus to enter the brain. The germs assault the parenchyma of the brain and multiply, causing inflammation of the brain. Invasions are typically linked to immunocompromised states because the pathogenic elements need to get past the strong defenses encircling the brain. The immune-stimulating expression and immune-suppressing chemokines and cytokines, as well as nerve cell activation by fungal cells, therefore, control FIs- CNS pathogenesis. Fungal invasion results in involvement of the CNS, cerebral and subarachnoid areas, and the BBB. Numerous factors, for example, surgery, microglia activation, cytokines can disrupt BBB, which helps this process. TNF harms the BBB’s TJs (Charalambous et al. 2018). The fungus’s virulence and the host immune system’s activity both affect how quickly and severely an infection spreads. Through the production of cytokines, chemokines and superoxide anion, as well as through the MHC I and II molecules expression, astrocytes, and ECs, these cells all significantly contribute to the prevention of infection (Gavito-Higuera et al. 2016).
14.6.1 Invasion of C. neoformans into the CNS The primary clinical manifestation of cryptococcosis, meningoencephalitis, is caused by the brain invasion of the neurotropic pathogen C. neoformans. According to Dando et al. (2014), the BCSFB and BBB are both possible entry routes for
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viruses and bacteria that cause neurotropic illnesses (Dando et al. 2014). Furthermore, few clinical instances in human patients of choroid plexitis were reported ted (Hammoud et al. 2017) which shows that passing via BCSFB only leads to minimal role into the CNS during cryptococcal dissemination. Instead, cryptococci clusters have frequently been discovered near the brain and cerebellum cortical microvasculature (Charlier et al. 2005), demonstrating that C. neoformans can breach BBB and invade the brain (Chen et al. 2022).
14.7 Conclusion In this chapter, we have explored the process of pathogen neuroinvasion, taking into account the evolving understanding of the CNS architecture and the molecular mechanisms governing interactions and responses between CNS and compartments of blood. Numerous bacteria have demonstrated the ability to infiltrate the CNS, and any organism that enters the CSF can potentially cause meningitis. Additionally, various fungi, bacteria, and viruses evolved intricate strategies to breach both the BBB and the BCSFB by exploiting transcellular and paracellular transport or utilizing the Trojan horse route. Many pathogens that affect the CNS exploit cell surface receptors present on brain microvascular ECs to gain access to the neurovascular unit or to enter the spinal cord and brain through intercellular pathways. For example, Neisseria meningitidis employs mechanisms involving attachment to fibronectin via the outer membrane protein Opc and binding to CD46 on HBMEC through pili. Escherichia coli adheres to choroid epithelial cells on luminal surfaces and ependymal cells lining the ventricles of the brain. By conducting further research on the pathogenicity and genetics of S. pneumoniae and C. neoformans, we can gain valuable insights into their evolutionary history, global dissemination, and the specific factors contributing to their pathogenicity in humans. This research is of utmost importance as it helps define the fundamental mechanisms of microbial pathogenesis, facilitating the design of novel strategies to manage microbial threats effectively. Thus, the investigation of pathogen neuroinvasion sheds light on the complex ways microbes interacts with and infiltrate the CNS, highlighting the significance of understanding these processes to develop effective approaches for combating infections and safeguarding human health.
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Muscular Dystrophy: Mutations in the Dystrophin Gene
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Aishwarya Agarwal, Kunal Verma, Shivani Tyagi, Khushi Gupta, Satish Kumar Gupta, Shrestha Sharma, and Shobhit Kumar
Abstract
Muscular dystrophy (MD) is a heterogeneous group of genetic disorders characterized by progressive muscle degeneration and weakness, leading to significant morbidity and mortality. Among the various forms of MD, mutations in the dystrophin gene have emerged as a pivotal contributor to the pathogenesis of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). The dystrophin gene, located on the X chromosome, encodes a large cytoskeletal protein critical for maintaining the structural integrity of muscle fibers. This chapter comprehensively explores the current state of knowledge regarding MD and its association with mutations in the dystrophin gene. Moreover, the chapter provides an overview of the clinical manifestations, genetic basis, and underlying molecular mechanisms that underpin the development of MD. Keywords
Muscular dystrophy · Dystrophin gene · Duchenne muscular dystrophy · Becker muscular dystrophy
A. Agarwal · K. Verma · S. Tyagi · K. Gupta · S. Kumar (*) Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, Uttar Pradesh, India e-mail: [email protected] S. K. Gupta School of Pharmaceutical and Population Health Informatics, DIT University, Dehradun, Uttarakhand, India S. Sharma Amity Institute of Pharmacy, Amity University, Haryana, Gurugram, Haryana, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_15
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15.1 Introduction In the 1830s, Sir Charles Bell was a certified neurologist and professor at the University of Edinburgh. He was noted for his work on the nervous system, which included an essay discussing a disability responsible for weakness experienced by boys, especially at an early age, which would intensify over time. A few years later, another scientist claimed to have discovered another instance involving two brothers who exhibited identical symptoms. These symptoms involved muscle weakness and the irreversible replacement of damaged muscles with accumulations of fat and connective tissue at specific locations. During this time, the symptoms were considered to be of other ailments like pneumonia that had become prominent due to the Industrial Revolution. Later in the 1850s, several clinical cases of young boys experiencing severe weakness and strength loss during adolescence, showcasing symptoms such as gait abnormalities that ultimately lead to an untimely demise, started making rounds in the news headlines and medical journals. A decade later, Guillaume Duchenne, a French neurologist, became the first person to provide a detailed account of this disorder. Duchenne, who had previously studied various nerve and muscle functions and their effects, examined 13 young boys and observed a similar severity of muscle weakness throughout their bodies (a condition later named Duchenne muscular dystrophy). He eventually presented his medical results in his book named “Paraplegie hypertrophique de l’enfance de cause cerebrale.” Muscle Dystrophies (MD) are described as a group of genetically heterogeneous disorders that manifest themselves in early childhood, leading to the degression of the musculoskeletal system. They result in various pathological shortcomings, such as atrophy, fibrosis, weakness, and loss of overall muscle coordination progressively over time (Gambelli et al. 2023). Upon studying their clinical etiology, it is found that they are caused due to the presence of defective or absence of various glycoproteins, particularly dystrophin (Matsumura and Campbell 1994). The deficiency of the protein is caused due to the mutations occurring on the gene that encodes the protein. Dystrophin, in its genetic form, is composed of a coding sequence of 79 exons and makes up to 2.5 Mb of DNA (Gao and McNally 2015). It is described as an essential part of a protein complex known as the costamere, which connects the scattered network of muscle fibers to the sarcolemma. Dystrophin is present in the muscle fibers, particularly in striated and cardiac types. It is also present in the muscles of the brain and eyes (retina). The costamere complex is responsible for providing sturdiness to muscle fibers and protecting them during periodic contractions and relaxations, preventing internal trauma or lesions. People with MD lose the ability to perform various motor functions, such as walking, sitting, ease of breathing, and movement of limbs in their daily lives. Certain chemical levels, such as creatine kinase (CK), exercise intolerance, dilated cardiomyopathy, malignant hyperthermia, speech delay, and Turner syndrome, are elevated asymptomatically in MD.
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MDs are mostly inherited through the X chromosome, and most people affected are clearly male. The daughter is thought to be a carrier of the symptomatic condition, which can be explained by Turner syndrome, inactivation and translocation of the mutant gene to an autosome, or uniparental causes. In most cases, the condition is presumed to be present in symptomatic females during infancy. Based on the theoretical data, MDs generally consist of copious variations. Various factors, such as the pattern of inheritance, the first instance of disease, and the rate of muscle loss, play a key role in defining the difference among the categories. Different depictions are present in the affected body. The mutations occurring in the gene are said to have two major origins of development; either inheritance from either parent or spontaneous occurrence during its progression throughout the body. Muscular dystrophies are said to be of contrastive inheritances (Table 15.1). Categorized upon the severity inhabited and symptoms exhibited, over 30 disorders are grouped under MD. The diagnosis for the specific type is done by conducting a physical examination of the patient and by carrying out several tests, including muscle biopsy, electromyography, gene testing, and studying the increased creatine phosphokinase (CpK3) of the patient. Various kinds of MD affect different muscle groups. Duchenne muscular dystrophy (DMD) accounts for half of the known cases. The other remaining types such as Becker muscular dystrophy (BMD), Facioscapulohumeral muscular dystrophy, and Myotonic dystrophy have common occurrences. The following figures are relayed for a general population consisting of almost a million. Table 15.1 Different types of inheritance patterns seen in MD (National Institute of Neurological Disorders and Stroke 2023) Types of inheritance Autosomal dominant inheritance Autosomal recessive inheritance
X-linked recessive inheritance
Inference and discussion In this scenario, the baby inherits a faulty gene from one of the parents who carries the gene for it. In such families, the kid has a 50% chance of acquiring the gene, resulting in developing the disease. It is equally dangerous for both genders, but the degree varies between individuals. In this scenario, the parents carry the recessive gene. Such parents, however, remain unaffected by it. Offspring of such parents either receive both copies of the recessive gene (25%) or acquire one gene that makes them carries themselves and can pass it on to their children (50%). This inheritance pattern is also not biased toward one gender. This kind of inheritance is sex-linked, which means that a mother is the carrier of the faulty gene, which is present on one of her two chromosomes and is inherited by her. Offspring of such carriers have a 50% risk of inheriting the condition. Daughters are in danger since they may inherit the recessive X chromosome. However, in most cases, it is observed that they usually receive the healthy X chromosome from their father, which cancels out the flawed one. Thus, they do not suffer any consequences. The affected father’s daughters will become carriers of the condition.
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• Childhood muscular dystrophy—7.1 cases in males and 2.8 in the general population. • Adult muscular dystrophy—8.26 cases. • Facioscapulohumeral dystrophy—3.95 cases. • Limb-girdle muscular dystrophy—less than 1.63 cases. • Congenital muscular dystrophies—approx. 0.99 cases. MD is uncommon, with few statistics and information available about the community or people affected by it. The majority of illness prognosis is found in early infancy; however, the episode might occur at any age. The Center for Prevention and Control of Diseases (CDC) is striving to produce estimates for persons suffering from MD. For a total population of about a million people • Prevalence of MDs in the general population: 15–25 cases • Frequency in general population: 1 • Incidence in male births: nearly 200 cases The problems of MD vary depending on the kind. Some are minor, while others are severe and rapidly worsen. Muscle weakness can impair one’s ability to move, breathe, swallow, and communicate. Possible complications include: • Airway constriction may occur due to the weakening of the breathing muscles. • Scoliosis. • Cardiovascular ailments that result in heart failure and require the insertion of a pacemaker. • Difficulty in swallowing can occur as the muscles in the esophagus are weakened. Some people end up being dependent on a feeding tube. • Contractures. • Vision problems leading to cataracts. • Need for a wheelchair. Regardless, persons who live with MDs have a chance of having virtually typical lives, as long as problems are adequately overseen and clinically addressed. In most of the conditions, the conditions become fatal for the patient leading to many of them meeting their demise before the age of 30 years. Due to chronic cardiovascular and pulmonary ailments being developed in the late adolescent period and early 20s of overall patients, only 25% of them make it out alive and even then, can only survive until the age of 21. In abundant cases, it is observed that children with DMDS are tempted by various complications leading to falling victim to their deaths before even hitting the next decade. However, there are certain rare cases in which some can make it past their 20s, despite the overall condition being lethal. Walker-Warburg syndrome is said to be one of the severe forms of MDs that can lead to death within the first year of age. Patients living with BMD similarly experience low life expectancy but most patients, if given the right medical care and treatment, can make it past the fourth or fifth decade.
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Undeterred by all the new treatments and interventions, there has not been a replacement treatment found for any sort of MD as a means to cure it and thus, it cannot be prevented. However, there are abundant methods to manage the symptoms and be able to continue living easily with this disorder. Surgical interventions such as defibrillator, shoulder surgery, and spinal correction can be executed to improve muscular movement in the specified area in the musculoskeletal system. Physical therapy and supportive braces are suggested to provide some ease in daily motor requirements in movements and improve strength for the major muscle networks to prevent complications and guide the patient to gain back their ability to walk without the need for any assistance. Medical interventions can include the administration of steroids and certain dosage forms meant to treat arrhythmia, epilepsy, and inflammation that can arise as side effects due to the effect on various muscles. Genetic counseling is recommended as the offspring of carrier parents, regardless of gender, have almost half the possibility of inheriting the gene.
15.1.1 Symptoms of MD A significant indicator of MD is the consistent deterioration of the skeletal muscle over an extended period. As a result, the strength to walk will eventually be lost. Some varieties are identified in infancy or youth while others are unable to be manifested until the individual reaches middle age. Various MDs can be identified on their significant etiology on which they differ in terms of whom they affect, the muscles they impact, and the symptoms they cause. The most common set of biological effects seen are listed below: • • • • • • • •
Falls regularly Struggling during change of postures while sitting or lying down Stumbling during walk Difficulty in movement of fibularis longus Enlargement of gastrocnemius muscle Pain and soreness Training barriers in motor representations Demotion in growth rate
Immediate medical diagnosis should be the first response while commencing the treatment for MD. When the disorder is further progressed, leading to the condition getting worse, the following complications are observed: • Difficulty during walking: People with MD will be eventually required to be dependent on a wheelchair at some point. • Difficulty during movement of limbs: Daily activities cause issues due to the rotator cuff and triceps muscles being compromised. • Shortening of tendons or muscles: Contractures around joints can further impede the movement of the body.
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• Breathing complications: The muscles involved in breathing might suffer from continual deterioration. People with MD may require a breathing assistance device (ventilator) at night and further increasing their dependency even during the day. • Scoliosis: Rapid muscle weakness also affects the erector spinae muscles causing difficulty in securing the upright position of the spine. • Heart issues: MD can impair the definitiveness of the myocardium, which can lead to various cardiac disorders. • Problems in swallowing: Deficiency of various nutrients and dysphagia may arise if the muscles in the esophagus are harmed. Feeding tubes might be used in such cases.
15.1.2 Various Types of MD As we discussed MD comprises several disorders observed to perform regressive bimolecular functions like muscle weakening and degeneration. The symptoms of a person’s MD might be minor, developing slowly throughout an average life span, depending on the kind and severity of the disease. In some circumstances, it can be aggressive, spreading swiftly and reducing a person’s life. DMD is the most widely occurring out of all MDs. Following up next is the BMD. However, numerous other types can arise at various times of life and progress at varying progressive rates (LaPelusa and Kentris 2023; Botta et al. 2007; Zernov and Skoblov 2019; Mahmood and Jiang 2014).
15.1.2.1 Duchenne Muscular Dystrophy (DMD) DMD is considered the most frequent and severe category of MD in children, compensating for almost 50% of all MD cases. It is said to be a sex-linked illness since it primarily targets male patients in comparison to females. This condition is caused due to the presence of a regressive gene on the 23rd, or the X chromosome, that results in the body failing to create a functioning muscle protein called dystrophin. DMD is more common in men, particularly between the age of 3 and 5. It advances quickly due to which most DMD patients lose muscle strength by the age of 12. They may eventually require a wheelchair to walk and a respirator to breathe. The majority of females, who possess the genetic abnormality, remain unaffected. Despite this, they have the probability of passing the condition on to each of their sons. Muscle weakness typically manifests in the upper legs and pelvis, which commonly develops between the ages of 2 and 6. Symptoms become more noticeable as the kid grows older. People with DMD can face death either in their late teens or early twenties due to various cardiovascular issues, pulmonary issues, or infections. In recent years, advances in medical care have allowed many people with DMD to live into their 30s or even 40s.
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15.1.2.2 Becker Muscular Dystrophy (BMD) BMD, like DMD, is caused by the dystrophin gene but differs in the severity of etiology. It is, likewise, a sex-oriented condition caused by the presence of a faulty gene on the X chromosome. However, some functional dystrophin can be generated. It primarily affects male patients between the ages of 11 and 25. The progression rate can range from either slow or fast. With certain limits and care, people with BMD can function well in adulthood. Some patients may never require the use of a wheelchair, whilst others may depend on it due to the loss of ability to walk later in life. 15.1.2.3 Myotonic Muscular Dystrophy (MMD) MMD is cause due to weakened Dystrophia Myotonica Protein Kinase (DMPK). It is considered to be the most prevalent variant of MD in adult patients, affecting between the ages of 20 and 30. However, it can also manifest among youngsters in rare cases. Myotonic MD is classified into two types: type 1 (the most frequent) and type 2. Types 1 and 2 are caused by a genetic mutation on separate chromosomes, which result in faulty RNA. Myotonia, or muscular stiffness after usage, is the predominant symptom where muscles are unable to relax after a rapid contraction. This type of MD carries the possibility of experiencing chronic cardiac complications. Individuals with MMD may end up requiring a pacemaker after the manifestation of the disease. 15.1.2.4 Facioscapulohumeral Muscular Dystrophy (FSHD) The name of FSHD refers to the body areas affected by this particular type, i.e., the facio meaning face, sapula meaning shoulders, and humeral meaning upper arms. FSHD frequently manifests itself by first affecting the eye muscles (difficulty in opening and shutting the eyelids) followed by those present in the mouth (inability to grin or pucker the lips). Symptoms might range from minor to becoming profoundly incapacitating. It is most commonly observed during adolescence but can develop as late as the age of 30. The majority of persons with such dystrophy live normal lives. It can be inherited as an autosomal dominant trait. 15.1.2.5 Limb-Girdle Muscle Dystrophy (LGMD) This kind of MD primarily affects both men and women beginning in early infancy throughout their adolescence or later in early adulthood. LGMD either precedes fast or slow, but the majority of people become severely crippled due to muscle degeneration by 20 years of age after being diagnosed. It is often inherited as an autosomal recessive trait. Cause deficiency in various proteins mainly in calpain, sarcoglycan, and dysferlin. The nine kinds of MD are listed in Table 15.2. Each variety differs in the muscles afflicted, the age at which it appears, and the rate at which it progresses.
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Table 15.2 Different types of MDs
Congenital
Manifestation Teenage-early childhood At birth
Duchenne
2–6 years
Distal
40–60 years
Emery-Dreifuss
Between childhood and early adolescence Between childhood to early adult Between late infancy to 40 years of age Between 20 and 40 years of age
Type Becker
Facioscapulohumeral
Limb-Girdle
Myotonic
Oculopharyngeal
Between 40 and 70 years of age
Description Less severe and progresses more slowly. The survival rate is through middle age. General muscular weakness and possibly joint abnormalities; progression is sluggish; life span is limited (Romero and Bitoun 2011). Muscle weakening and damage across the body; Gradually impact the muscles of the arms and lower body; Survival beyond the age of 20 is uncommon. Only seen in boys (Mercuri et al. 2019). Muscle weakness and atrophy throughout the arms and legs; seldom lead to absolute inability. Muscular and joint abnormalities are rather prevalent. The progression is sluggish. Sudden death is possible. Facial muscular weakness that affects shoulders and upper arms; moderate effectiveness and fast deterioration (Van Der Maarel et al. 2012). Weakness in the shoulder girdle and pelvic girdle; sluggish advancement; and cardiopulmonary problems can cause death. All muscular groups are affected starting with the face, feet, and hands, and ending with the neck. The progression rate is sluggish, taking 50–60 years at times. Affects the muscles of the eyelids and throat, resulting in the inability to swallow; development is considered to be sluggish.
15.1.3 Disease Mechanism The muscles in our bodies, such as the calves’ muscles, are made up of longitudinal cells that contain muscle fibers. These fibers are responsible for the execution of muscular contraction and relaxation. When comparing the image and structure of a healthy muscle to a muscle undergoing pseudo hypertrophy, there is a buildup of fat and connective tissue present in it, eventually leading to the muscle looking large but being extremely weak in strength. The CNS is not involved during the pathogenesis of MD in the body but rather a mutation in the dystrophin gene on the X chromosome. Dystrophin exists as a protein that acts as a support beam for muscle cells in humans. This, along with the other components of the dystrophin-associated protein complex, i.e., DAPC, connects the intracellular cytoskeleton to the extracellular matrix of the cell. It protects the muscle cells from any damage that can be caused by the tension produced during the regular contraction of muscles. It is linked to the contractile element of the muscle fiber, actin, and is coupled to the β-dystroglycan that is entrenched with a large set of proteins in the sarcolemma, a specialized
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membrane that encapsulates the muscle fiber. Furthermore, it is connected to the connective tissue of the muscles. For the sarcolemma to properly transit to higher muscles, it creates a variety of forces. When a muscle cell lacks dystrophin or has a damaged dystrophin owing to cell membrane injury, the muscle cell becomes feeble. This lack of dystrophin causes extracellular calcium ions to enter the muscle fibers. This results in an increase in cystolic calcium levels. The elevation in calcium levels causes the ubiquitously present calpain to get activated. These calpains further stimulate the proteolysis pathway, causing muscular necrosis and atrophy. The loss of essential enzymes such as CK occurs due to the leakage of cells. After exiting the cell membrane, CK accumulates in the bloodstream. Elevated CK levels found in blood are an early indicator of muscle injury. A growing share of genes have been identified that, when modified, result in abnormal glycosylation of α-dystroglycan (a component of the DAPC). Since glycosylation is essential for α-dystroglycan to couple with its protein binding partners, defective processing breaks these connections. This makes the muscle fiber more sensitive to the damage and thus initiates the dystrophic process. Fragile nuclei can also lead to MD, as evident by the effects of mutant emerin, lamin A, and lamin C, all of which are proteins found at the nuclear membrane (Davies and Nowak 2006). A schematic mechanism of MD is shown in Fig. 15.1.
Fig. 15.1 Mechanism of MD
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15.1.4 Mutation of Gene Dystrophin When it comes to chromosomes, the male has a set of one X chromosome and one Y chromosome, while females have a set of two X chromosomes. When an X chromosome mutation occurs, men are left defective but females have another X chromosomes to compensate for the flawed one, rendering them asymptomatic. This is why 1 in 3500 men suffers from MD than females. Dystrophin is encoded by the DMD gene, which spans 2.4 megabases at locus Xp21 and is the biggest known human gene. The dystrophin gene is made up of 79 exons that encode the components of proteins that are crucial to the muscle’s function and general health. The structure of the exons may be compared to distinct train carriages stacked one on top of the other. The vast majority of dystrophin gene mutations include full exon deletions or multiple contiguous exon deletions. During transcription, each exon can only connect to a certain type of other exon. The reading frame rule states that not all exons are compatible with one other, which applies to 90% of the cases. As the DNA code is read in a “triplet by triplet” manner, dystrophin synthesis is required to maintain this reading frame throughout the entire length of the gene. If particular deletions function in such a way that the loss occurs as a multiple of three base pairs, the reading frame may remain intact upstream and downstream, resulting in the formation of some modified dystrophin. There are two ways by which a mutation takes place:
15.1.4.1 Frameshift Mutations Frameshift mutations are mutations that disrupt the reading frame. When the reading frame is broken, the translation produces shortened, unstable dystrophin or no protein at all. 15.1.4.2 In-Frame Mutation In-frame mutations occur when a mutation does not disrupt the reading frame. These exons’ translation allows muscle cells to produce tiny quantities of partly functional proteins. Since the dystrophin gene is present as one of the biggest genes in our body, it is prone to mutations (changes) more than an average type of gene. It has been found that thousands of distinct mutations can take place in the singular dystrophin gene. The reading frame rule, however, cannot be always considered as the ideal criteria. Some out-of-frame deletions can induce BMD, whereas others cause Duchenne- type dystrophy. Sometimes, a kid’s diagnosis will remain uncertain until the youngster gets older for the progression and manifestation of the disease to be followed. Duchenne and Becker’s muscular dystrophies are caused by deletions of one or more exons of the dystrophin DMD gene. The three main types of mutation that take place on the Dystrophin gene are the following (Love et al. 1990, 1991; England et al. 1990).
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• Large deletions: Deletions happen when sections of the gene (called exons) are missing. The most frequent form of mutation is the deletion of one or more exons. Since the dystrophin gene contains 79 exons, several types of deletions can occur. Some parts of the gene are more prone to have a deletion. Such sites are known as “hot spots.” Exons 44–55 are considered high-risk areas for such deletions. • Large duplications: These types of changes are caused when one or more exons of a gene are doubled. Duplicates are less prevalent in comparison to deletions. Duplications, similar to deletions, can occur throughout the 79 exons of the dystrophin gene. • Point mutations: This type of mutation involves minor alterations in the gene and does not encompass a full exon as part of the process. Sometimes only one letter of the DNA sequence is removed, multiplied (duplicated), or modified. A nonsensical mutation is one of the most prevalent types of point mutation. Nonsense mutations cause the gene to stop working prematurely, resulting in little or no dystrophin protein synthesis. MD progresses uniquely for each individual, therefore each person living with this disease exhibits a particular set of etiology, regardless of any genetic mutation. Even the siblings that exhibit similar types of mutation may experience an extremely varied symptom development. The symptoms of this condition progress on a range starting with late-onset, showcasing mild effects to early onset with severe symptoms. Genetic testing is currently the go-to method for the diagnosis of DMD and BMD. It reveals the type of mutation that exists, as well as the specifics of that particular mutation. Genetic testing can further help to identify whether a person is more likely to develop Duchenne or Becker syndrome. But, as previously indicated, the forecasts of severity based on the given mutation are not considered ideal with symptoms and illness progression to be taken into consideration as well. As a result, families must contact their doctor for a definitive diagnosis. Intermediate individuals may have characteristics that lie between Duchenne and Becker (Gambelli et al. 2023).
15.1.5 Current Strategies for Muscular Dystrophy Therapeutics The presently available treatments for MD aim at reducing the severity and management of symptoms that are manifested in the body. Ongoing therapeutic research including some gene-based methods, shows a promising decrease and even reverse of some symptoms of specific kinds of MD. Although advances in patient care and illness management have delayed disease progression, current drugs are unable to halt the unrelenting loss of muscle structure and function that leads to early death. Current therapy approaches can be split into two categories. Dystrophin-targeted therapy methods that aim at restoring the dystrophin expression and/or its function. The other classes of therapy techniques aim at enhancement of the muscle function
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and quality. They achieve it by analyzing the underlying pathological alterations, such as inflammation, fibrosis, and muscular atrophy. However, the therapeutic benefits of downstream particular therapy are not completely consistent, and their precise pathways are unknown. It is preferable to have an elaborative knowledge of the subsequent pathological alterations to create more effective treatments.
15.1.5.1 Dystrophin-Targeting Strategies Gene therapy, cell therapy, and protein replacement therapy are all examples of dystrophin-targeted therapeutics. Despite extensive preclinical and clinical research, such targeting therapeutics face several obstacles while performing their action. The main concern of such strategies is for the therapies to only postpone the course of DMD and not to restore the function of aberrant muscle tissues owing to the degenerative nature of DMD. Second, because muscle tissue is numerous and extensively dispersed throughout the body, it is challenging during the therapy to target all muscle tissues. As a result, increased emphasis has been made on the enhancement of muscular function by addressing the downstream and degenerative alterations of the DMD (Happi Mbakam et al. 2022). Gene-Based Therapy Gene-based therapy techniques offer the possibility of providing long-term MD patients with one-time treatment. In this, the deleted exons are concentrated in the area between exon 43 and exon 55, accounting for around 60–65% of the occurrences. Several gene-based therapeutic techniques have been developed, including: • • • •
Exon-skipping Stop codon and read through Gene-addition Gene-editing therapy
Drug Therapy Many classes of drugs can help to prolong muscle deterioration or entirely alleviate the symptoms of MD. Some examples are as follows: • Glucocorticoids: Prednisone and deflazacort are some examples of glucocorticoids. Prednisone drugs given regularly provide results that include improvement in muscular strength and respiratory function, as well as help in halting the progression of weakening in muscles. In boys with DMD, a novel glucocorticoid therapy called Vamorolone is revealed to have similar advantages to prednisone but without any negative effects (Moxley et al. 2005; Sheehan et al. 2018; Sreetama et al. 2018). In animal studies, Vamorolone was also observed to help to alleviate the symptoms of LGMD. • Anticonvulsants: These drugs, which are often used to treat epilepsy, may help persons with MD control seizures and certain muscular spasms.
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• Immunosuppressants: Immunosuppressive drugs help to prevent any further harm to the degenerative muscle cells in MD. • Beta-blockers: Drugs like Angiotensin-converting enzyme (ACE) inhibitors are linked with the treatment of some types of MD, including high blood pressure and heart failure. Cell-Based Therapy Cell-based treatments use normal muscle progenitor cells to introduce normal genomes into dystrophic muscles (Sun et al. 2020). The optimal cell source can help to transfer an intact DMD gene to influence both limb muscles and the heart (Ramos and Chamberlain 2015). In animal research and clinical trials, many kinds of stem cells have been used to study DMD. In test animals, satellite cell transplantation from muscle biopsies increases dystrophin expression (Xu et al. 2015). Protein Replacement Utrophin is found to be an autosomal structural and functional paralog of dystrophin (Loro et al. 2020). It has been recommended as a replacement for dystrophin due to its comparable structure and function (Guiraud et al. 2019). Modified expression of a full-length Utrophin, upon testing on animals such as mdx mice, can help to prevent the onset of MD (Péladeau et al. 2018). As a result, increasing the Utrophin levels in DMD patients is considered as a viable therapy (Makar et al. 1975).
15.1.5.2 Strategies Based on Secondary Downstream Pathological Mechanisms These tactics are based on several pathogenic pathways that are activated by dystrophin depletion (Birnkrant et al. 2018). Fibrosis, inflammation, loss of calcium homeostasis, oxidative stress, ischemia, and muscular atrophy are some examples of it. In addition to treatment efforts aimed at restoring dystrophin functioning, drugs targeting the downstream pathological alterations that can be produced by dystrophin deficiency are gaining popularity. Fibrosis-Targeting Strategies In DMD, fibrosis is a significant pathological alteration (Zhou and Lu 2010). Fibrosis is characterized as an unrestrained and detrimental wound-healing process produced by persistent tissue injury and long-term immunosuppression (Wynn 2007). It is distinguished by an abnormal accumulation of extracellular matrix (ECM) proteins (Wynn 2008). Fibrosis is the major cause of mortality in DMD patients and can affect any tissue or organ. Fibrogenic cytokines can induce tissue fibroblasts to produce ECM proteins (Suntar et al. 2020). This process is aided by transforming growth factor (TGF), connective tissue growth factor (CTGF), and tumor necrosis factor (TNF) (Walker et al. 2019).
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Inflammation-Targeting Strategies An increase Ca2+ promotes fiber necrosis and, consequently, a severe inflammatory response (Allen et al. 2016). This mechanism is predominantly mediated by the NF-kB pro-inflammatory pathway (Altamirano et al. 2012). The NF-B pathway is regulated by TNF- and IL-6, which are responsible for the formation of the I-B kinase (IKK) catalytic complex subunits (De Pasquale et al. 2012). NF-B activation can result in p50/p65 translocation into the nucleus and subsequent transcription of genes encoding cytokines and immune response proteins (Baldwin 2001). Strategies Based on Muscle Damage Dysregulation of Calcium Ions
DMD patients are found to have elevated resting and active Ca2+ levels in their myofibers (Law et al. 2020). Excess cytosolic Ca2+ can worsen dystrophic disease further by boosting Ca2+-dependent proteinase cleavage of intracellular proteins (Townsend et al. 2007). Streptomycin can be used as a non-specific Ca2+ channel blocker (Makar et al. 1975). Upon experimentation in mdx mice, long-term Streptomycin treatment was found to improve limb muscle pathology by decreasing fibrosis, enhancing sarcolemmal integrity, and encouraging muscle regeneration (Whitehead et al. 2006). AT-300 (GsMTx4) is another Ca2+ channel blocker that can precisely block mechanosensitive calcium channels and boost muscular force output while lowering muscle degeneration (Bush et al. 2017; Yeung et al. 2005). Loss of Bone Mass
In MD, osteoporosis is caused by several causes, including long-term glucocorticoid therapy, reduced physical activity, the development of dystrophin-deficient triggered cytokines, and a lack of vitamin D (Buckner et al. 2015; Mah 2016). Pamidronate and Zoledronic acid are two bone metastasis treatment drugs that may be able to stabilize or perhaps improve the height of compressed vertebrae in prepubertal DMD patients and decrease back pain (Yang and Du 2015).
15.2 Conclusion In conclusion, this chapter has provided a comprehensive overview of the role of mutations in the dystrophin gene in the pathogenesis of MD, with a particular focus on DMD and BMD. Emerging gene-editing technologies and gene replacement therapies hold tremendous potential for addressing the root cause of these disorders and providing hope for patients and their families. The ongoing clinical trials investigating these innovative approaches offer optimism for the future. Nevertheless, the challenges of developing effective treatments remain, including addressing issues of scalability, delivery, and long-term efficacy. By bridging the gap between scientific knowledge and clinical practice, we can aspire to translate the latest discoveries into
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tangible treatments, bringing us closer to the day when MD becomes a condition effectively managed and, ultimately, conquered.
References Allen DG, Whitehead NP, Froehner SC (2016) Absence of dystrophin disrupts skeletal muscle signaling: roles of Ca2+, reactive oxygen species, and nitric oxide in the development of muscular dystrophy. Physiol Rev 96:253–305 Altamirano F, López JR, Henríquez C, Molinski T, Allen PD, Jaimovich E (2012) Increased resting intracellular calcium modulates NF-κB-dependent inducible nitric-oxide synthase gene expression in dystrophic mdx skeletal myotubes. J Biol Chem 287:20876–20887 Baldwin J (2001) Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest 107:3–6 Birnkrant DJ, Bushby K, Bann CM et al (2018) Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol 17:347–361 Botta A, Vallo L, Rinaldi F et al (2007) Gene expression analysis in myotonic dystrophy: indications for a common molecular pathogenic pathway in DM1 and DM2. Gene Expr 13:339–351 Buckner JL, Bowden SA, Mahan JD (2015) Optimizing bone health in Duchenne muscular dystrophy. Int J Endocrinol 2015:1. https://doi.org/10.1155/2015/928385 Bush E, Ward C, Suchyna T, Sacks F, Blaustein M, Escolar D (2017) AT-300, a calcium modulator, improves muscle force production and decreases muscle degeneration in D2-mdx model of Duchenne muscular dystrophy. Neuromuscul Disord 27:S192 Davies KE, Nowak KJ (2006) Molecular mechanisms of muscular dystrophies: old and new players. Nat Rev Mol Cell Biol 10(7):762–773 De Pasquale L, D’Amico A, Verardo M, Petrini S, Bertini E, De Benedetti F (2012) Increased muscle expression of interleukin-17 in Duchenne muscular dystrophy. Neurology 78:1309–1314 England SB, Nicholson LVB, Johnson MA, Forrest SM, Love DR, Zubrzycka-Gaarn EE, Bulman DE, Harris JB, Davies KE (1990) Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 343:180–182 Gambelli CN, Bredin J, Doix A-CM, Garcia J, Tanant V, Fournier-Mehouas M, Desnuelle C, Sacconi S, Colson SS (2023) The effect of tibialis anterior weakness on foot drop and toe clearance in patients with facioscapulohumeral dystrophy. Clin Biomech 102:105899 Gao QQ, McNally EM (2015) The dystrophin complex: structure, function, and implications for therapy. Compr Physiol 5:1223–1239 Guiraud S, Edwards B, Babbs A, Squire SE, Berg A, Moir L, Wood MJ, Davies KE (2019) The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy. Hum Mol Genet 28:2189–2200 Happi Mbakam C, Lamothe G, Tremblay JP (2022) Therapeutic strategies for dystrophin replacement in Duchenne muscular dystrophy. Front Med (Lausanne) 9. https://doi.org/10.3389/ FMED.2022.859930 LaPelusa A, Kentris M (2023) Muscular dystrophy. StatPearls Law ML, Cohen H, Martin AA, Angulski ABB, Metzger JM (2020) Dysregulation of calcium handling in Duchenne muscular dystrophy-associated dilated cardiomyopathy: mechanisms and experimental therapeutic strategies. J Clin Med 9. https://doi.org/10.3390/JCM9020520 Loro E, Sengupta K, Bogdanovich S, Whig K, Schultz DC, Huryn DM, Khurana TS (2020) Author correction: High-throughput identification of post-transcriptional utrophin up- regulators for Duchenne muscle dystrophy (DMD) therapy. Sci Rep 10. https://doi.org/10.1038/ S41598-020-60885-8
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Gene Editing Tool for Neurodegenerative Diseases
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Mohd Yasir Khan, Hamda Khan, Farah Maarfi, Afreen Khanam, Ziaul Hasan, and Arbab Husain
Abstract
Neurodegenerative diseases (NDs) encompass a heterogeneous group of disorders characterized by the progressive degeneration and death of neural cells, as well as synaptic dysregulation in specific regions of the nervous system. These conditions, such as Alzheimer’s and Parkinson’s disease, are increasingly prevalent and have significant neurological implications, impacting millions of individuals worldwide. Various factors, including disrupted autophagy, signaling abnormalities, oxidative stress, mitochondrial dysfunction, impaired neurotrophins, and cytokines, contribute to the misfolding and aggregation of proteins, which are significant markers of NDs. Despite the growing prevalence of NDs, there is currently a lack of precise diagnostic tools and effective treatments for these conditions. However, recent advancements in genome sequencing and editing have opened up new possibilities for addressing these challenges. Emerging gene-editing tools (GETs), such as CRISPR-Cas9 and zinc finger nucleases (ZFNs), offer promising potential for correcting defective genes or DNA, leading to the restoration of lost neural function and connectivity. Furthermore, the inte-
M. Y. Khan · F. Maarfi Department of Biotechnology, School of Applied and Life Sciences (SALS), Uttaranchal University, Dehradun, Uttarakhand, India H. Khan Department of Biochemistry, Jawahar Lal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India A. Khanam · A. Husain (*) Department of Biotechnology and Life Sciences, Faculty of Sciences, Mangalayatan University, Aligarh, Uttar Pradesh, India Z. Hasan Department of Biosciences, Jamia Millia Islamia, New Delhi, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_16
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gration of GETs with stem cell technology (SCT) holds tremendous prospects for advancing our comprehension of human genetics, regenerative medicine, and the biological mechanisms implicated in NDs. The present chapter aims to explore the main influential factors associated with NDs, providing a comprehensive overview of their evolutionary trajectory, methodology, molecular mechanisms, and applications of GETs. This knowledge serves as a foundation and forms the basis for developing preventive and targeted strategies against NDs. By leveraging the potential of gene editing, we can advance our understanding of the complexities surrounding NDs and improve the quality of life for affected individuals. Keywords
Neurodegenerative diseases · Misfolded protein · Neural death · Gene-editing tools · Regenerative medicines
16.1 Introduction Neurodegenerative disorders (NDs), including Parkinson’s, Alzheimer’s, and Huntington’s, are considered to be the most dreaded maladies worldwide. It is estimated that ~7 million people in America suffer from NDs. By the year 2050, it is projected that this number will double, reaching around 14 million individuals suffering from NDs (Zhao 2020). NDs occur due to the progressive failure of neuronal networks that eventually leads to the death of neurons and dysregulating motors, cognitive, and sensory functions. According to WHO, it is possible that by 2050, NDs will surpass cancer in terms of ranking among the diseases that cause death. Several awareness programs are being conducted, and the Government has already established new policies, but to date, no specific diagnostic tools, effective therapies, or treatments are available against NDs. Unfortunately, current pharmacological treatments provide only temporary symptomatic relief (Menken et al. 2000). Recent data related to protein biochemistry suggests that cellular, genetics, or alternated signaling processes leading to the abnormal and uncontrolled aggregation of misfolded proteins, impaired ubiquitin-proteasome system, apoptosis/autophagy, and free radical generation are the underlying causes behind synaptic loss and pathological feature of NDs (Fan et al. 2018). The underlying concept relies on targeting and manipulating small segments of these endogenous aggregation-prone proteins, with the ultimate goal of attenuating their pathologic activities by gene editing. Moreover, different conventional editing approaches, including RNA interference and homologous recombination (HR), have already been applied, which majorly focuses on gene expression, gene silencing, or inducing gene knockouts. However, they come with several drawbacks and unpredictable off-target effects due to difficulty in multiple gene transfection, RNAi-based mutant variability, unstable knockouts, and the generation of unwanted mutagens among other factors (Qiu et al. 2005; Fan et al. 2018).
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Recent advancements in GETs have emerged as powerful tools in biological research for treating NDs and showing promising results in inhibiting disease progression. One demanding aspect of GETs is the ability to induce a targeted DNA double-strand break (DSB) in the specific sequence of interest. The three widely used procedures of GETs, able to induce DSBs are Zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), CRISPR (clustered regulatory interspaced short palindromic repeats)-Cas9 (CRISPR-associated), bags promising and valiant breakthrough in the modification of defective gene, epigenetic modulation and transcriptional control (Carroll 2017). Secondly, it is assembled using Stem Cell Technology (SCT), such as human-induced pluripotent stem cells (hiPSCs), which have the potential to overcome ethical and safety concerns. This technology holds implications for scientific research and potential therapies targeting incurable diseases (De Masi et al. 2020). The principle goal of this chapter is to focus on a detailed study of the different GETs debilitating diseases, and their prospects in connection to SCTs.
16.1.1 Overview and Historical Background of CRISPR CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). To protect themselves from the invasion of foreign DNA like a bacteriophage, bacteria develop an adaptive immune system in the form of a CRISPR-DNA sequence. This technology provides modification in genomic sequences that are identified through guide RNA (gRNA), which is stretchable, and by CRISPR, they can be modified virtually. Due to this, the clear-cut function of disease-causing genes becomes clarified, along with other processes such as rectifying the mutations that cause disease, inhibiting oncogenes, or restoring the function of cancer suppressor genes that are deactivated when utilizing a nuclease-deficient Cas9 and effector domain as a fusion protein. Besides this, various gene functions can be assessed consecutively by CRISPR at several genomic loci, which helps to understand the progression of tumors and the pathological process of mutation. Additionally, CRISPR-Cas9 shows a great ability for the treatment of genetic disorders, from cancer and neurodegenerative diseases (NDs) to cardiovascular diseases, including sickle cell anemia, cystic fibrosis, and viral infections (Bhardwaj et al. 2022). Generally, the genomes of prokaryotes and bacteria carry repeating DNA sequences with CRISPR loci and Cas9 proteins, which make up the CRISPR system. Cas protein induces a DSB, working as a nuclease, cutting at a particular site. It has been suggested that the working function of RNA interference is similar to some extent to that of the CRISPR-Cas system, where mRNA is cleaved by protein complexes (Makarova et al. 2006). In 1987, the Japanese scientist Yoshizumi Ishino and his team discovered CRISPRs in E. coli by accidentally cloning a unique collection of repetitive sequences with spacer sequences inserted while examining the gene that is responsible for the conversion of alkaline phosphate (Ishino et al. 2018). According to the studies that were conducted in the Netherlands under J.D. van Embden in 1993, he discovered that Mycobacterium tuberculosis has various spacer
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sequences between its DNA repeats. Spoligotyping is a technique used to characterize M. tuberculosis strains depending on the spacer sequence (Sola et al. 2015). These sequences were subsequently also found in numerous other archaeal and bacterial genomes and were termed CRISPRs by Franscisco Mojica and Ruud Jansen (Morange 2015). Streptococcus pyogenes provided the Cas-9 protein that was first used to alter a genome (SpCas-9). The genetic scissor is a big (1368 amino acids) multi-domain DNA endonuclease that cleaves the target DNA to create a double- stranded break (Mei et al. 2016). CRISPR-based GETs emerged in 2012 and have since become crucial and dominant in the field of biology due to their targeted and precise manipulation of DNA sequences. It has gained a crucial, dominant, and important role in living biology (Capecchi 2005). The research related to CRISPR technology has been summarized in the timeline history of CRISPR in Fig. 16.1.
16.1.1.1 CRISPR Classification and Its Components CRISPR/Cas9 systems based on the structure and functions of Cas proteins are classified into two classes mentioned in Fig. 16.2 (Mir et al. 2018). The type II CRISPR/ Cas9 system is one of the most used and studied systems in the production of pharmaceutical development within Class 2. Class 1 systems have multi-subunit Cas-protein complex domains. Class 2 only utilizes Cas-proteins. Since the structure of type 2 CRISPR/Cas-9 is relatively simple, it is easily studied in genetic engineering (Liu et al. 2020). CRISPR-associated (Cas-9) proteins and gRNA together comprise crisper loci and are considered essential parts of the CRISPR/Cas-9 system. Cas-9 The nuclease (NUC) and recognition (REC) lobes are the two regions that constitute Cas-9. The NUC lobe consists of RuvC nuclease, Protospacer Adjacent Motif (PAM) interactions domain, and HNH nuclease domain. The REC lobe is made up
Fig. 16.1 Timeline of CRISPR-based research
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Fig. 16.2 Classification of CAS-9 system
of REC1 and REC2 domains that are responsible for binding gRNA. Each single- stranded DNA is sliced by the RuvC and HNH domains, while the PAM interaction domain confers PAM specificity and starts binding to the target DNA (Nishimasu et al. 2014). Guide RNA Sequences for trans-encoded short CRISPR RNA, or trans-activating crRNA (tracrRNA), and sequences for non-coding RNA elements known as CRISPR RNA (crRNA). Single guide RNA (sg RNA), a complex made up of the two RNA sequences crRNA and tracrRNA, controls how specifically the target region in the nucleic acid is cut (Karvelis et al. 2013; Jinek et al. 2012). The tracrRNA is a long stretch of loops that serve as an interacting and binding region for Cas-9. While crRNA is 18–20 bp in length and pairs with the target sequence, In prokaryotes, the gRNA specifically targets viral DNA and is synthetically engineered as sgRNA by combining crRNA and tracrRNA to target all the possible genomes required to be edited (Mei et al. 2016). Cas9-mediated nicks and breaks in dsDNA all happened with the activity of HNH and RuvC nuclease domains; this domain performs perfect cuts in the target strand as well as in the non-target strand. Two separate lobes, the alpha-helical recognition (REC) and nuclease lobe, which consist of reserved HNH and RuvC nuclease domains and adjacent variable C-terminal domains (CTD), appear in the Cas9 structure in the apo state. These lobes are ligated by two linker sequences: one is arginine rich and the other is disordered. Three alpha-helical domains constitute the REC lobe, which are Hel-I, Hel-II, and Hel-III; furthermore, the CTD contains PAM interaction sites that are important for PAM integration. From comparison with homologous structures of DNA-bound nucleases, the Cas9 nuclease RuvC signifies structural similarity with the characterization of the RNase H fold, which belongs to the retroviral integrase superfamily, and also reveals the use of metal ions by them to cleave the non-targetDNA-strand (Jinek et al. 2014; Nishimasu et al. 2014).
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Target DNA is cleaved through one-metal ion mechanism activity, which is adopted through the one-metal fold of the HNH nuclease domain. Establishing perfect cleavage by site-specific DNA recognition requires an active DNA surveillance complex, which forms when Cas9 assembles with an RNA guide (a native crRNA, tracrRNA, or sgRNA). TracrRNA has a pivotal role in the Cas9 service; on the other hand, the 20-nt spacer sequence of crRNA confirms DNA specificity (Jinek et al. 2014). When the interaction establishes between crRNA and gRNA, the mechanisms extend to search the complementary target DNA sites; this only happens when both target and recognition have complementary base pairing between the 20-nt spacer sequence and a protospacer in target DNA, with the reserved sequence in the PAM (Karvelis et al. 2013). PAM sequences are important due to their activity in identifying self and non-self-sequences, and a single mutation in PAM will disrupt the Cas9 cleavage (Marraffini and Sontheimer 2010). The mechanisms of recognition elucidate the PAM duplex structure; in this duplex structure, a sharp kink turn is found in the target strand, which is necessary for driving the target DNA strand to attach to gRNA. After this, the activation of Cas9 leads to DNA cleavage. As stated earlier, the two domains are used by Cas9; they work by forming a blunt end DSB at target dsDNA at a specific site (3 bp from the NGG PAM sequence). However, a single-strand break results from the one-strand DNA duplex being broken by the Cas9 nickases.
16.1.1.2 Molecular Mechanism of CRISPR/Cas9 System-Based Editing “Bacterial Defense Mechanism” against phage infection and plasmid transformation, has been repurposed, engineered, and utilized as a powerful platform that is based upon RNA-guided DNA for genome editing (Fig. 16.3). The three-step mechanisms of CRISPR/Cas-9 genome editing are recognition, cleavage, and repair (Ming et al. 2016) • Recognition: Through the complementary base pair component 5′crRNA of Cas-9 directed by the designed sgRNA, detects the target sequence. • Cleavage: Due to the absence of sgRNA, hence Cas-9 protein acts as an idle. DNA double strands get incised through the Cas-9 nuclease which broke the strands, following the target gene sequence at a site 3 base pair upstream to PAM (Ceasar et al. 2016) at 5′-NGG-3′ (where N is any nucleotide base), formation of RNA-DNA hybrid took place by DNA melting, however by what means targeted DNA sequence meltdown from the activity of Cas-9 was enigmatic. To produce predominantly blunt-end DSBs, both HNH and RuvC domains perform the cleavage activity. The HNH domain cuts the complementary strand, while the RuvC excises the non-complementary strand (Mei et al. 2016; Kim et al. 2015). • Repair: After that, the blunt-end DSBs are repaired by the Cas-9 protein’s cellular machinery by using the two pathways (Mei et al. 2016; Kim et al. 2015). (a) Non-homologous end joining (NHEJ) (b) Homology-directed repair (HDR)
Fig. 16.3 Bacterial defense mechanism: CRISPR array with Cas genes and trans-activating CRISPR RNA (tracrRNA) essential for pre-crRNA processing as well as target recognition, cleavage, and repetitive sequences. When the interference takes place, the viral plasmid’s DNA is integrated in the array (CRISPR array) by the Cas operon (Cas1, Cas2, Cas2n) and gets transcribed, where tracrRNA separate from the main sequence, during transcription, allows the transcribed tracer RNA to join the 3′-pre-crRNA leading to the crRNA maturation, cleavage of main sequence by unknown nuclease enzyme which shortens the sequence into different fragments and encapsulated in by Cas-9 endonuclease and causes site-specific cleavage preceding PAM sequence
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The working mechanism of NHEJ is insertion/deletion, which causes gene inactivation by premature stop codon and/or DNA frameshifts, whereas the activity of HDR is to replace the mutated/faulty sequence with the correct one, and this starts with the donor DNA template, and right DNA sequence subsume at the desired site (Bhardwaj et al. 2022). Moreover, there is a restriction to HDR in the G/S phase, but not for the NHEJ, which can occur in every cell cycle phase. Because of its lower efficiency in comparison to the NHEJ pathway, the HDR pathway gives highly efficient DNA repair mechanisms (Bhardwaj et al. 2022).
16.1.1.3 CRISPR/Cas9 Gene Editing System Assisted Management and Treatment of NDs Gene editing using the CRISPR-associated proteins 9 system (CRISPR/Cas9) has gained interest because it may be useful in the management and treatment of NDs. This newly developed technology is simple, affordable, and precise, which has raised interest in this method among NDs. This can be applied as a direct therapeutic strategy or may help to develop more accurate animal models that accurately reflect human NDs. A plethora of reports suggests that this technique has a promising role in NDs, including Alzheimer’s Disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). CRISPR in Alzheimer’s Disease AD is a progressive and irreversible chronic ND that shows a greater impact at the social and economic level (Kumar et al. 2015). Accumulation or aggregation of β-amyloid (Aβ) along with many other misfolded proteins, hyperphosphorylated fibrillar tangled tau protein, and increased glial cell leading to neuron loss, is a potent marker of AD progression. It is being manifested that the pathophysiology of AD is more closely linked to genome modification. Recent advancement in CRISPR/ Cas9-mediated genome editing provides a better approach against early-onset familial AD and AD management. A plethora of reports on CRISPR as a genome editor in the treatment of AD has been available. In a study by György and his colleague, this system helps knock out Swedish APP mutations in patient-derived fibroblasts finding a 60% Aβ reduction (Mullan et al. 1992; György et al. 2018). For more targeted delivery of CRISPR/ Cas9, several viral such as plasmids and viruses, including adeno-associated virus and non-viral vector system, have been dynamically used in several experimental models. Such vectors are cost-effective, easy to handle, feasible, and flexible, with a high tendency of infectivity, minimum immunogenicity, and integration into the human genome (Gaj et al. 2016). Another mode is via nano complexes which are formed by coupling negatively charged nucleic acid cargo with positively charged CRISPR/Cas9 peptides. They can help in many applications and, in comparison to viral vectors, are less immunogenic. They also work with ligands. Nanocomplexes are difficult to administer systemically because they cannot adequately cross the blood-brain barrier (BBB), and the reticuloendothelial system (RES) actively eliminates them from circulation (Table 16.1).
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Table 16.1 Table showing different genes targeted by CRISPR technology in the treatment of AD Targeted genes The C-terminal sequence of APP
Mode of delivery CRISPR/Cas9 delivered via lentivirus
Model studied HEK293-neuro2a cells, dentate gyrus C57BL/6 mice
APP
(FAD)AD APP mutations
In vitro
APP
APP(SW) CRISPR/Cas9 system
KM670/671NL APP (APPswe) mutation
CRISPR/Cas9 delivered via recombinant adeno- associated virus
APOE E4
CRISPR/Cas9 delivered via lentivirus
Isolated from APP(SW) transgenic mouse embryos (Tg2576) Co-injection into the hippocampus of adult mice APPswe fibroblasts in primary neural cells from humans are used to create embryos that are then implanted into the hippocampi of Tg2576 mice 3xTg mouse model
APOE E4 (converting it into APOE3r)
Cytidine deaminase conjugated CRISPR/Cas9 plasmids
HEK293T cells line-immortalized mouse astrocytes
Major outcomes Attenuating β-cleavage and Aβ, while upregulating neuroprotective α-cleavage Mutations IN L52P, T48P and K53N generation, APP mutations which cleavage of γ-secretase and the Notch signaling Elimination of Swedish mutation and decreased ex vivo and in vivo, peptide synthesis
Reference(s) Sun et al. (2019)
The relevance of adopting a gender-specific focus
Tozzo et al. (2020)
The goal is to knock out Casp6 activity using the CRISPR/ Cas9 system and alleviate pathological degradation caused due to activated pathways This eliminates the expression of ApoE4 which prevents the development of sporadic AD
Offen et al. (2018a)
Xu et al. (2016)
György et al. (2018)
Offen et al. (2018b)
(continued)
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Table 16.1 (continued) Targeted genes Thioredoxin- interacting protein (Txnip) PSEN2
BACE1
MAPT
PSEN1M1
APPS
APP
Mode of delivery Generated mutation in PSEN2 assessed insulin signaling Decreased Aβ42/40 ratio, PSEN2 mutation
Model studied HT22 cells
Major outcomes Inhibits amyloid-β- induced protein cysteine oxidative modification Insulin acts as a mediator of resilience by working as an antagonist of specific metabolic in AD Manipulation in Aβ-linked disease, a significant reduction in Aβ42 plaque in the mice NHEJ leads to exon removal and forms a new Tau knockout strain (tauΔex1) in mice Generation of disease models and HDR-mediated modification
Reference(s) Wondafrash et al. (2020)
Human-induced pluripotent stem cell
HDR-mediated mutation
Paquet et al. (2016)
In vitro
Reciprocate amyloid pathway manipulation Inhibits β-cleavage and Aβ production
Sun et al. (2019)
iPSC-derived neuronal subtype: the basal forebrain cholinergic neurons (BFCNs)
Target Bace1 and suppressed amyloid beta (Aβ) associated pathologies New tau knockout strain generated by CRISPR
Two mice models of AD
Cas9 introduces targeted (DSBs) with high efficiency that are repaired by (NHEJ) AD causes a mutation in amyloid precursor protein and derived cortical neurons Cas9 has double-stranded breaks in DNA and custom – designed single-guided RNA that targets Cas9 at host genomic DNA
Human-induced pluripotent stem cells
Mapt in C57BL/6J mice
Moreno et al. (2018)
Park et al. (2019)
Tan et al. (2018)
Paquet et al. (2016)
(continued)
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Table 16.1 (continued) Targeted genes PSEN2
PSEN1
APOE
GMF
APP
GSAP
BACE and Th
APOE
Mode of delivery Reported the generation of i-PSC-derived neurons and mutation in PSEN1 Val97Leu missense mutation of presenilin-1gene in FAD pedigree Fusion of CRISPR and cytidine deaminase enzyme without breaking dsDNA and conversion occur GMF gene editing leads to the inhibition of GMF expression and suppression of microglial activation into murine cell lines A protective deletion mutation in 3′-UTRof amyloid precursor protein. GSAP affects vesicular APP trafficking APP first by β-secretase and γ-secretase complex In AD patients carrying the E4 allele is corrected by E3 with Cas9 system
Model studied The cell line of presenilin 2
Major outcomes N141I generation, normalizes Aβ42/40
Reference(s) Ortiz- Virumbrales et al. (2017)
Presenilin-1
Met146Val generation
Fang et al. (2006)
In human cell and murine cell lines
Conversion of APOE E4 to APOE E3, Arginine158 to cysteine 158 in 58.0–75.0%
Komor et al. (2016)
In vivo
Reduction in Glia maturation factor and p38 MAPK
Raikwar et al. (2019)
NL-G-F MOUSE
3′-UTR amyloid precursor, reduction in APP and Aβ
Nagata et al. (2018)
Transfection
Reduction in γ-secretase activating protein Reduction in BACE1, Th1 and Aβ
Wong et al. (2019)
Reduction in APOE-E3/E4
Wadhwani et al. (2019)
Clinically in mice
In the stem cell-derived neurons
Zhang et al. (2011)
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CRISPR in Parkinson’s Disease After AD, the second most fatal disorder that is still incurable is PD, a neurodegenerative disorder that directly attacks the central nervous system and leads to unruly movements, such as shaking, stiffness, strenuous with balance and rhythm, which only get worsen with the time and bids other symptoms of depression, sleep problems, memory difficulties and many more (Kalia and Lang 2015). The most prominent sign of PD is the loss of dopaminergic neurons, which are present in the substantia nigra part of the midbrain. This degeneration leads to a deficiency of dopamine in the basal ganglia, which is responsible for and involved in the regulation of muscle movement. Aggregates of misfold α-synuclein protein, also named Lewy bodies, are common determinants of PD (Poewe et al. 2017). Furthermore, at the bottom of the pathophysiological PD, manifests in familial and sporadic forms. The first studies of genetic linkage of PD signify the part of synuclein alpha (SNCA) mutation and in the familial form of PD pathogenesis SNCA genomic duplication. Following further research, another thing that came to the light is leucine repeat kinase-2 (LRK-2) mutation. Prominent reasons which may be responsible for making it hard to unbreak the mechanisms of pathogenic are due to a great extent, to numeral mutations. These are associated with mendelian autosomal dominant (AD), SNCA, LRK-2, VP535, HTRA2, EIF4G1, GBA, autosomal recessive (AR) inheritance- PARK2, PINK1, PARK7 (DJ-1), ATP13A2, PLA2G6, and FBX07. Interpreting the contribution of these genetic variants and establishing their interconnections with PD is a challenging task (Kouli et al. 2018). However, CRISPR/Cas9 may be quite promising and used to study PD by establishing research models, which can help in future therapy. The linkage between the SNCA gene of numeral degeneration in the region of SN, Kantor, and colleagues developed an approach based on an epigenetic therapeutic which targets the SNCA’s regulation. They make a system of CRISPR-deactivated Cas9 (dCas9) which combines with the DNA-methyltransferase 3A catalytic domain (DNM+3A), from which they downregulated SNCA m RNA and protein in hiPSC from a PD patient, after which, this downregulation of SNCA level due to CRISPR Cas 9 tool, gives a new approach against PD (Kantor et al. 2018). An in vitro and in vivo study of the CRISPR-Cas9 tool was conducted by Hyung Ho Yoon et al., to delete the A53T-SNCA, where in vitro, he examined that the expression of A53T-SNCA decreases gradually by an AAVS consisting RNA (single-guided) and SAC ds9-KKH that attacks the A53T-SNCA. Further, they expand their research on the rat model of pH, which is overexpressing the viral A53T-SNCA. The conclusion was the drastic reduction in the overexpression of α-synuclein, motor symptoms, and reactive microgliosis after A53T-SNCA genes were deleted. Another study was conducted by Y Chen et al., which laid down the SNCA−/− and SNCA+/− cell lines through CRISPR Cas 9n by removing the SNCA gene, which codes for α-synuclein in the hESC line. The outcome is that the heSC’s line is transformed into mtDNA neurons, and these recombinant neurons promote inhibition to lewry pathology, which strengthens the use of CRISPR/ Cas9n-mediated to remove the SNCA alleles opposition to PD in a host-to-graft transfer (Yoon et al. 2022).
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CRISPR-Cas9 mosaicism, a Rhesus macaque model, CRISPR/Cas9-mediated PINK1 deletion, generated through in which they observe the SN region’s neuronal reduction, allowing the researchers to understand the complexity of other phenotypes. Several other researches have been done, like to understand the neuroinflammatory mechanisms related to PD. Protein kinase Cδ (PKC δ) signaling associated with Mn-induced apoptotic cell death in PD involves PKC δ downregulation in the DA neurons (Song et al. 2019). We can see as a gene editing tool CRISPR/Cas9 has an immense characteristic of correcting the specific gene sequences and hence can be utilized magnificently in the treatment of AD and other diseases, however, several challenges are linked together in the CRISPR/Cas9 tool therapeutics and in the treatment of AD and PD management, which only sort out by further researches (Table 16.2). Table 16.2 Table showing different genes targeted by CRISPR technology in the treatment of PD Targeted genes A53T- SNCA
Mode of study A53T-SNCA- specific PD
LRRK2
G2019S is hypothesized to increase LRRK2 kinase activity
PINK1
Primate model with PINK1 deletion
Main outcomes – Adeno-associated virus carrying SaCas9- KKH with single-guided RNA targeting A53T- SNCA significantly reduces A53T-SNCA expression level (in vitro) overexpression rat model of PD. – LRRK2 G2019S mutation and truncation of LRRK2 kinase domain into marmoset embryonic and human- induced pluripotent stem cells. – Phenotypic evaluation demonstrated increased intracellular reactive oxygen species and decreased neuronal viability. – Robust neuro- degeneration in various brain regions in the model. PINK1 is essential for neuronal survival in primate brains.
Model study In vitro and rat model of overexpressing A53T-SNCA
References Yoon et al. (2022)
Human-induced pluripotent stem cells, marmoset embryonic cells
Sahlol et al. (2020)
Genetically modified rodent model
Yang et al. (2019)
(continued)
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Table 16.2 (continued) Targeted genes DJ-1 (PARK7)
Mode of study Zebrafish
ATP13A2 (PARK9)
ATP13a2 deficient zebrafish
Htra2
Htra2 gene disrupts to inhibit aminoglycosides deafness via CRISPR-Cas9
PARKIN
Physiological regulators of PARKIN abundance pooled genome- wide CRISPR/Cas 9 knockout screen
Main outcomes – CRRISPR/Cas9 used to target exon 1 of PARK7−/− gene to produce a transgenic DJ-1 deficient zebrafish model. – Normal development of PARK7−/− line at young adult and larval stage, but with aging, DJ-1 null fish exhibit lower tyrosine hydroxylase levels, and respiratory failure in skeletal muscle. – Proteomic analysis of the early adult brain, shows less than 5% of 4091 identified proteins involved in mitochondrial metabolism, mitophagy, and stress response is influenced by lack of DJ-1. – Dopaminergic neuron degeneration, lysosomal dysfunction, and intracellular trafficking impairment are the key pathogenic mechanisms in Parkinson’s disease. – CRISPR/SpCas 9 system ameliorates neomycin-induced apoptosis via AAV, hair cell survival, and better function of hearing in neomycin-treated mice. – THAP11 negatively regulates endogenous PARKIN abundance. – THAP11 CRISPR knockout in multiple cell types enhanced phosphor S65-ubiquitin (pub) accumulation.
Model study Zebrafish model to modulate cellular signaling causing neuro- degeneration
References Edson et al. (2019)
ATP13A2 deficient zebrafish model
Nyuzuki et al. (2020)
Neomycin- treated mice
Gu et al. (2021)
Human-induced pluripotent stem cells
Potting et al. (2018)
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16.1.1.4 Future Perspectives in the Treatment and Management of NDs There are diverse challenges in the treatment and management of NDs. CRISPR/ Cas9 bags major promises by targeting specific gene sequences. In PD/AD, altered protein metabolism either due to amino acid modification or/and mutation in genes such as PARK2, DJ-1, PINK1, or SNCA, APP, PSEN-1, and PSEN-2 could easily be manipulated using CRISPR/Cas9 technology (Kolli et al. 2018). Through vector systems, the management and treatment of AD and PD can be conducted by CRISPR /Cas9 gene editing technique. To select a vector, which is suitable for the process must be stable, resistant to lysosomal degradation, and have the efficient gene- carrying capacity to deliver it in a particular site (Xu et al. 2020; Karimian et al. 2020; Schneller et al. 2017). The circulating nucleases/proteases, the component of the generated formulations are reported to be vulnerable to degradation. In comparison to plasmid-assisted transfer, more preferred is Cas9-sgRNA as of smaller sized complex. Studies targeting off-targets and long-term effects are still insufficient in terms of data and face ethical issues. Furthermore, the CRISPR/Cas9-based study only affects somatic cells rather than germlines hence giving scope only to the manifested individual undergoing treatment (Tozzo et al. 2020). From the reprogramming mechanism, pluripotency is generated in somatic cells (iPSCs). Further, iPSCs have been shown vital ability to get better control of safety and ethical issues concern to embryonic stem cells (Takahashi and Yamanaka 2006). The reinforcement of this technology in translational therapies against NDs displays a more efficient and targeted approach. Isogenic cell lines are developed for in vitro models of disease and cell therapy which are related to a correct point mutation in hiPSCs derived from Ataxia-Telangiectasia by CRISPR/Cas9 approach (Ovchinnikov et al. 2020). However, many challenges need to be pondered upon. In particular, improved reprogramming mechanism, establishment of standard protocols inhibition of de novo mutations, and improved target accuracy with the help of pluripotent stem cells. Furthermore, safety assurance of CRISPR/Cas9-assisted therapeutics is required, as genome editing is an irreversible process (De Masi et al. 2020). However, several safety aspects need to be evaluated for human trials related to CRISPR/Cas9 in the future. Another perspective is a translation of these studies to preclinical and clinical studies to gain more mechanistically targeted research with less cost and greater efficiency.
16.2 Introduction to Zinc Finger: Gene Editing Tool One of the most prevalent protein families, zinc finger proteins (ZNFs), have a variety of molecular roles. Zinc fingers may have begun as peptides, which preserved a straightforward structure. ZNFs can interact with DNA, RNA, PAR (poly-ADP- ribose), and other proteins due to the large range of zinc finger domains. It is one of the most prevalent structural motifs in eukaryotic cells and is used in some of their most significant proteins, including Transcription factor IIIA (TFIIIA), CCCTC- binding factor (CTCF), and zinc finger-containing transcription factor 268 (ZiF268).
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Up to 37 ZNFs domains are present in these DNA-binding proteins, which are linked together by adaptable linker regions (Takatsuji 1999). Engineered ZFNs can effectively introduce desired insertions, deletions, or substitutions at or near the cut site via homology-directed repair (HDR) with a double- and/or single-stranded donor DNA template. ZFNs cause DNA DSBs at specific recognition sequences. The preset zinc finger modules, which were chosen via phage display, were put together to create the DNA-binding domains. When an endonuclease domain was fused with a transcriptional activation domain, it produced bespoke nucleases that were assessed for their capacity to trigger HR in episomal and chromosomal gene repair tests. This enabled the measurement of DNA binding in reporter experiments (Alwin et al. 2005). Plant zinc finger proteins are distinguished by lengthy, variable- length spacers between adjacent fingers and a highly conserved sequence. Classical ZNFs containing proteins, which are encoded by 2% of human genes, make up the largest family of sequence-specific DNA-binding proteins. The proteomes of numerous different animals contain the ZNF domain, which allows various proteins to interact with or bind DNA, RNA, or other proteins. It has been discovered that proteins with ZNF domains perform critical roles in eukaryotic cells by regulating various signal transduction pathways and managing processes like development and programmed cell death. The largest class of ZNF motifs is the C2H2-type ZNF motif (Gupta et al. 2012). C2-H2, C2-CH, and C2-C2 are examples of nonclassical cysteine/histidine pairings that distinguish ZNF types. The HUGO Gene Nomenclature Committee has accepted 30 different ZNF types as of right now, and the zinc finger domain structure serves as the basis for ZNF classification. In the past two decades, mounting evidence has suggested that C2H2-type ZNF proteins are crucial for plants’ ability to withstand abiotic stress. Prior work has attempted to categorize zinc-binding sites in proteins according to the type of ligands that bind zinc and the shape of the ligands, as well as the ZNFs themselves (Krishna et al. 2003). There are four types of C2H2-type ZNF proteins found in plants: (1) single- C2H2 proteins; (2) triple-C2H2 [tC2H2] proteins; (3) proteins containing more than three adjacent C2H2 ZNFs (multiple-adjacent-C2H2 [maC2H2]); and (4) proteins containing several C2H2 ZNF pairs that are widely separated (separated-paired- C2H2 [spC2H2]) (Han et al. 2020). The structural classification of ZNFs is as follows: • • • • • • • •
Fold group 1: C2H2-like finger Fold group 2: Gag knuckle Fold group 3: treble clef finger Fold group 4: zinc ribbon Fold group 5: Zn2/Cys6-like finger Fold group 6: TAZ2 domain-like Fold group 7: short zinc-binding loops Fold group 8: metallothioneins
Among the most prevalent proteins in eukaryotic genomes are ZNFs proteins. They perform a wide range of tasks, such as lipid binding, transcriptional activation,
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apoptotic regulation, DNA recognition, RNA packing, and RNA packaging. The majority of DNA-binding proteins in all spheres of life belong to the ZNFs protein family. Each ZNF motif interacts non-covalently with three or four DNA base pairs to detect specific target sequences. ZNFs are widely distributed in nature, and their modular structure may in part account for the enormous variability seen in a wide range of organisms, from yeast to humans. ZNFs function as independent folding structural building pieces in this sense, and they are frequently encoded by a single exon. Many transcription factors contain the ZNF protein, which is a common DNA-binding domain. It has about 30 amino acids and is capable of identifying three DNA base pairs. It can identify and bind to a particular DNA in the genome by combining three to six ZNF protein molecules. Although they are more frequent than expected, ZNF mutations may result from cancer-type-specific mutational signatures. We then looked for ZNF mutations in light of these cancer-specific mutational biases since many malignancies exhibit diverse mutational signatures. The largest transcription factor family in the human genome is composed of ZNF proteins. ZNF proteins can play a variety of roles in biological processes, such as development, differentiation, metabolism, and autophagy due to the varied combinations and functions of ZNF motifs (Jen and Wang 2016).
16.2.1 History and Discovery of Zing Finger The zinc finger was initially identified 15 years ago in Xenopus transcription factor IIIA (TFIIIA) as a repetitive zinc-binding motif comprising conserved cysteine and histidine ligands (Hall 2005). Since then, several other zinc-binding patterns have been discovered and given the name “zinc fingers.” These have a broad variety of functions, from DNA or RNA binding to protein–protein interactions and membrane connection. They also have a large range of structural variations (Cassandri et al. 2017). The traditional Cys2 His2 zinc finger is now acknowledged as the first member of a fast-growing family of zinc-binding modules. Any small, functional, autonomously folded region that needs the coordination of one or more zinc ions to sustain its structure is referred to as a zinc finger (Razin et al. 2012). Therefore, in the fall of 1985, Jonathan Miller, begin studying TFIIIA. This led to the discovery of a fascinating repeating pattern inside the protein, which we subsequently called zinc fingers in laboratory parlance because they contained zinc and clutched the DNA. Immature oocytes retain 5S RNA molecules in the form of 7S ribonucleoprotein particles (Klug 2005), each carrying a single 40-kDa protein that was subsequently revealed to be similar to TFIIIA (Layat et al. 2013). Because TFIIIA binds both 5S RNA and its corresponding DNA, it has been proposed that it may facilitate the autoregulation of 5S gene transcription (Cassiday and Maher 2002). Whether or not this autoregulation happened in vivo, the dual interaction presented an intriguing structural challenge that could be investigated due to the presence of high amounts of the protein TFIIIA in immature Xenopus oocytes (Croft 2004). Miller found extremely poor yields when he repeated the described techniques for purifying the 7S particle,
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which we ascribed to dissociation. Brown (1984), utilized buffers containing dithiothreitol (DTT), which was chosen since the protein had a high cysteine content, and/or EDTA to eliminate contamination from metals that hydrolyze nucleic acids. The complex was gel filtrated in 0.1 mM DTT, resulting in distinct elution of protein and 5S RNA. When it was discovered that the powerful reducing chemical sodium borohydride did not affect the complex, it was understood that the protein was not being kept together. When it was discovered that the powerful reducing agent sodium borohydride did not destroy the complex, it was concluded that the protein was not kept together by disulfide bridges and that a metal was involved. When the particle was incubated with a range of chelating chemicals, only the addition of Zn2+ before incubation prevented particle dissociation, not the addition of a variety of other metals. Atomic absorption spectroscopy analysis of a partly purified 7S sample indicated a considerable concentration of Zn, with at least 5 mol Zn/mol particle. During these experiments, Hanas et al. 1983, reported the presence of Zn in the 7S particle at a ratio of two per particle. This was an underestimation because their buffers contained 0.5 or 1 mM DTT, which has a high Zn binding constant of about 10. As a result, the analysis was repeated with pure and undissociated particle preparations, taking extra precautions to avoid contamination. The native 7S particle contains 7–11 zinc ions. This result was consistent with the fact that the protein contains large numbers of histidine and cysteine residues, the commonest ligands for zinc in enzymes and other proteins. This hinted at some kind of internal substructure (Jamieson et al. 2003; Rhodes and Klug 1993).
16.2.2 Structure and Function of the Zinc Finger The structure of the zinc finger is defined based on its classification. Its structure includes zinc with the coordination of histidine and cysteine. Structurally, it has been divided based on its domain, these are the BTB domain, SCAN domain, KRAB domain, and C2H2-zinc finger motif (Li et al. 2022).
16.2.2.1 BTB Domain It is also known as the POZ domain. It has protein–protein interaction found in whole eukaryotes. It acts in transcriptional regulation, cellular functions, and targeting proteins for ubiquitination. The BTB domain is a single-copy structure with a length of about 120 amino acids. It is connected to a number of other domains, such as the C2H2 zinc finger and Kelch domains. At least 49 mouse and human genes encode the BTB-ZF (broad-complex, tram track, and bric-a-brac zinc finger) proteins, which frequently act as sequence-specific silencers of gene expression. Forty- nine of the projected 156 human genes that code for proteins with the BTB domain also have a set of C2H2 zinc fingers (Siggs and Beutler 2012). • Function: Many BTB proteins are hypothesized to function as transcriptional regulators by influencing the chromatin structure. Its functions included regulat-
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ing B and T lymphocytes, BAZF/Bcl6b controlling proliferation, ROG/PLZP controlling T-cell activation and cytokine production, MAZR suppressing CD8 expression in early thymocyte development, cKrox/Th-POK controlling helper lineage commitment, ROG/PLZP controlling peripheral T-cell subset development, and Bcl6 regulating T-cell development (Bilic and Ellmeier 2007).
16.2.2.2 SCAN Domain A subfamily of C2H2 zinc finger proteins contains a highly conserved 84 residue pattern known as the SCAN domain. The leucine-rich region (LeR), often referred to as the SCAN domain, serves as a protein interaction domain that mediates self- association or selective association with other proteins. Some zinc fingers of the Cys2His2 type are connected to conserved protein domains that provide information about these regulators. The N-terminus of a subfamily of C2H2 zinc finger proteins contains the SCAN domain, a unique 84-residue motif that belongs to this type of domain (Edelstein and Collins 2005). • Function: SCAN transcription factors exhibit a wide range of biological activities, particularly in the development of cancer. ZSCAN transcription factors have recently been linked to abnormal expression in a growing number of cancer research. Notably, ZSCAN transcription factors might have opposite effects in cancer types, or even within the same cancer type. Additional roles included tumor suppressor, cell migration and invasion, and cell apoptosis (Huang et al. 2019).
16.2.2.3 KRAB Domain Krüppel-associated box-containing proteins, also known as zinc finger proteins, were first identified by Bellefroid et al. (1991). They are the biggest single family of transcriptional regulators in mammals, accounting for almost one-third (290) of the 799 distinct zinc finger proteins found in the human genome. It can be separated into subregions A and B, which are projected to fold into two amphipathic -helices. It is high in charged amino acids. Many KRAB proteins only include the A box and the KRAB-A and B boxes can be separated by various spacer regions (Urrutia 2003). • Function: The RNA polymerase I, II, and III promoters are transcriptionally repressed, RNA is bound and spliced, and nucleolus function is controlled by members of the KRAB-containing protein family. When bound to the template DNA by a DNA-binding domain, the KRAB domain performs the function of a transcriptional repressor. The transcription of the genes that KRAB-ZFPs bind to is repressed by the KRAB domain, which mediates protein–protein interactions through binding to corepressor proteins and/or transcription factors. A potent tool for suppressing gene expression is clustered regularly interspaced short palindromic repeat interference (CRISPRi), which is based on the fusion of dormant Cas9 (dCas9) with the Krüppel-associated box (KRAB) repressor (Alerasool et al. 2020).
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16.2.2.4 C2H2 Zinc Finger Motif One of the most prevalent domains in the TFs of higher eukaryotes is the C2H2 zinc finger (Cys2-His2). The left-handed structure of the traditional C2H2 domain, which has 28–30 amino acids, is made up of an antiparallel sheet made of two strands called a “hairpin” and a helix. The number of figures in C2H2 zinc finger proteins ranges from 1 to 30. Most proteins can be categorized into one of three types based on the number and arrangement of their fingers: triple-C2H2, multiple- adjacent-C2H2, and separated-paired-C2H2 finger proteins. Proteins having several contiguous C2H2 fingers can bind a variety of ligands, as opposed to proteins with triple C2H2 fingers. Proteins that have multiple separated pairs of fingers only use one pair to bind to the target (Iuchi 2001). • Function: With its widespread existence in people, animals, and plants, the C2H2 type zinc finger protein is the most well-known zinc finger transcription factor. The main functions of the identified plant C2H2 zinc finger proteins are growth, development, and stress responses in plants. C2H2 proteins specifically bind to lengthy DNA sequences spanning several tens of base pairs, in contrast to the well-studied transcription factors of other classes. Contrary to the majority of other TFs that bind to short palindromic sequences as homo- or heterodimers, the C2H2 proteins can efficiently attach to DNA as monomers. Several interactions with protein complexes, individual transcription factors, and RNAs can be made possible by specific C2H2 domains working in conjunction with the unstructured areas of C2H2 proteins (Fedotova et al. 2017).
16.2.3 Mechanism of Zinc Finger Targetable DNA cleavage agents called ZFNs have become popular gene-targeting agents. Cellular DNA repair mechanisms that are triggered by ZFN-induced DSBs frequently result in targeted gene replacement (Fig. 16.4) as well as targeted mutagenesis. The zinc fingers insert numerous a-helices into the DNA’s main groove to detect particular tri-nucleotide DNA sequences. The co-localization of the CCHH domains and the cooperative binding of a-helices enhance the specificity and strength of the protein-nucleic acid interaction. Every stage of the wound healing process, including membrane repair, oxidative stress, coagulation, inflammation, immunological defense, tissue re-epithelialization, angiogenesis, and fibrosis/scar formation, is significantly regulated by zinc (Carroll 2011). ZFNs served as model organisms in previous literature. Arabidopsis thaliana plants undergo specific alterations as a result of ZFNs. According to these findings, ZFNs will be effective tools for directing alterations in experimental organisms for functional studies and building models of human genetic illnesses. By creating DNA DSBs in target genes, which then activate the cell’s natural homologous recombination (HR) machinery, it increases the efficacy of gene targeting (Cassandri et al. 2017).
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Fig. 16.4 Zinc finger nuclease helps in gene targeting
Numerous zinc finger proteins of the C2H2-type activate transcription during plant growth and abiotic stress. Under circumstances like salt, drought, and low temperature, C2H2-type zinc finger proteins with ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motifs perform critical roles in controlling the expression of genes associated with abiotic stress (Han et al. 2020). The leucine-rich region sometimes referred to as the SCAN domain, serves as a protein interaction domain that facilitates self-association or selective association with other proteins. In angiogenesis, cell apoptosis, cell differentiation, cell migration and invasion, cell proliferation, stem cell qualities, and chemotherapy sensitivity (Fig. 16.5), SCAN zinc finger transcription factors may have favorable or discouraging effects (Porteus and Carroll 2005).
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Fig. 16.5 Possible role of SCAN zinc finger in different biological activities
16.2.4 The Activity of the Zinc Finger in the Brain ZNF selectively attaches to DNA and RNA in the human body’s many tissues, including the brain, where they operate as transcription factors to control how the human genome is expressed. Studies have shown that the GLIS family zinc finger 3 (GLIS3), ZFX belonging to the C2H2 family, and MSUT2 (ZC3H14) belonging to the CCCH-type family alter the neurofibrillary tangles via influencing the accumulation of tau proteins. It is known that the gene that GLIS3 belongs to is a risk gene for Type 1 and Type 2 diabetes, glaucoma, and the AD endophenotype. GLIS3 is a zinc finger protein that is related to tau protein and is highly expressed in islet cells (Scoville et al. 2020). Numerous C2H2-ZNFs play a crucial role in the above-mentioned neurogenesis process that is orchestrated by radial glial progenitor cells (RGCs). Mice with the Gli3 mutation have significantly decreased or stopped producing cortical neurons. Gli3, a poly-ZNF involved in sonic hedgehog signaling, regulates the RGCs’ cell cycle by altering the duration of the G1 phase. Their entire cell cycle is shortened by Gli3 inactivation, and delays in the maturation of cortical neurons and the cortical lamination process result (Al-Naama et al. 2020). Recent research has shown that zinc finger proteins have a pathogenic role in a number of neurodevelopmental diseases and cancers, but little is known about how these proteins may affect juvenile brain tumors (Kanakoglou et al. 2022). Various ZNFs are significantly involved in the regulation of specific expressions of the human genome to promote the development of the different parts of the brain (Bu et al. 2021). C2H2-type ZNFs functioned to control the sonic hedgehog signaling and control the cell cycle of radial glial progenitor cells, which are known to serve as the primary neural progenitor cells (Al-Naama et al. 2020). ZNFs also act as a repressor to reduce the mutant Huntington expression in the brain (Garriga-Canut et al. 2012). Therefore, ZNFs are frequently used in gene regulation to target the specified genes in the brain, such as tau protein levels in Alzheimer’s related damage. It is quite complicated to explain the underlying mechanism of the brain in the mediation of ZNFs since the brain and its system has an undefined complexity which is needed to explore to further proceed the experiment in the clinical world.
16.3 Other Gene Editing Tools We have already discussed in the previous sections that GETs, including CRISPR/ CAS, ZFNs, and TALENs, have emerged as a novel tool not only for generating specific ND animal models for interrogating the mechanisms and screening potential drugs against NDs but also for the editing sequence-specific genes to help
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patients with NDs to regain function and connectivity. Apart from these above- mentioned GETs, there are certain other tools also discovered so far that play some sort of role in connection to different diseases, and they are discussed below:
16.3.1 Restriction Enzymes With the discovery of restriction enzymes (RE) in the 1970s, the possibility of editing genes became a reality. RE are critical tools for recombinant DNA technology, which has transformed current biological research, yet their sequence specificity and availability are limited. RE are an important tool in genomic research because they provide a space for foreign DNA to be inserted for gene editing by cutting DNA at a specified location (Enghiad and Zhao 2017). The chance to insert additional DNA material at that position is provided by RE when they detect particular patterns of nucleotide sequences and cut at that site. Since RE are restricted by the nucleotide patterns they can identify, they are no longer often employed for gene editing, although they are still routinely used for molecular cloning. Additionally, specific kinds of RE are essential for building DNA libraries, mapping the epigenome, and mapping DNA (from restriction enzymes to CRISPR-Cas9 2022).
16.3.2 Base Editing Base editing, a relatively recent technique for modifying the genome, was developed from CRISPR-Cas9. Base editors (BEs) do not cause double-stranded breaks in the genome, in contrast to conventional CRISPR systems. The Broad Institute’s David Liu group created base editing devices that combine DNA deaminases with a “catalytically dead” Cas9 (dCas9), which cannot cleave DNA. While adenine deaminases, which cause A to G substitutions, were developed from bacterial enzymes, particularly for base editing, cytosine deaminases, which cause C to T substitutions, are found naturally in bacteria. Researchers can induce substitutions in DNA by fusing dCas9 to either a cytidine deaminase (CBEs) or an adenine deaminase (ABEs) and giving a sgRNA to direct it to the target sequence. Single nucleotide polymorphisms account for the bulk of human disorders, and the ability to generate single nucleotide changes was a significant advance for the science since it eliminates many of the possible hazards associated with other editing techniques like CRISPR-Cas9. Prime editing systems were created as a result of the problem that the present CBE and ABE systems only account for 4 of the 12 potential transition mutations (Monsur et al. 2020; Rees and Liu 2018).
16.3.3 Prime Editing Prime editing techniques permit all conceivable transition alterations as well as minor insertions and deletions of up to 50 and 80 nucleotides, respectively. The Cas9 nickase, which causes single-stranded breaks in DNA, is coupled to a
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reverse transcriptase enzyme in the system that was developed by the Liu laboratory. Prime editing employs a single designed construct called a prime editing guide RNA (pegRNA), which is made up of the primer binding site (PBS) sequence and a sequence carrying the desired edit, as opposed to a sgRNA and a donor template for repair. The reverse transcriptase utilizes the pegRNA as a template for reverse transcription and attaches the matching nucleotides to the nicked DNA end when the Cas9 nickase, having located the target, cuts a hole in one strand of the DNA. Endonucleases found inside the cell naturally remove the original sequence, but this leaves a mismatch between the two strands of DNA that has to be fixed in order for the editing to be finished. This is accomplished by instructing the primary editor to nick the opposite, unedited strand using a different gRNA. When this happens, the cell fixes the nick by utilizing the fresh DNA created by the first edit as a template, producing a full edit (Komor et al. 2018). Prime editing is significantly safer to utilize, which makes it very useful for therapeutic applications because it can produce all conceivable transition mutations, insertions, and deletions without causing DSBs. In addition to their many other potential therapeutic uses, BEs and prime editors (PEs) are presently being studied for the treatment of blood diseases, including sickle cell disease (Suh et al. 2022).
16.3.4 Programmable Addition Via Site-Specific Targeting Elements (PASTE) In terms of genome editing, PASTE is a relative newcomer. This technique, which was created by Jonathan Gootenberg and Omar Abudayyeh, enables the controlled insertion of lengthy DNA sequences without causing double-stranded breaks. Serine integrase proteins from bacteriophages are used by PASTE to ingest additional genetic material, up to 36 kb, into the genome. However, in order for this to function, the proper landing site (AttB), which is not frequently seen in genomes, must first be located and bound to by the integrase’s attachment site (AttP). To get over this problem, PASTE uses prime editing to reversetranscribe these AttB sites into the genome close to the target region. Conveniently, primary editing methods can splice in up to 50 bp of DNA, and integrases can detect AttB landing sites that are around 46 bp in length. The AttB site serves as a beacon for the integrase, which will be attracted to the site to carry out the insertion of the associated desired DNA sequence when it has been integrated close to the target region by prime editing. The creation of the PASTE tool is very promising for gene editing since it enables extensive gene knock-in without DSBs. This suggests that it may have therapeutic uses, such as the treatment of conditions brought on by several harmful mutations in big genes. The safety profile of any prospective therapeutic use of this technique is increased by PASTE’s capacity to edit DNA without generating DSBs, similar to base and prime editing methods (Mah and Roberts 2022).
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16.3.5 Challenges Associated with these GET’s Despite their recent development, RE, DNA BEs, and PEs have already been widely employed in medicinal applications and offer tremendous promise as a therapeutic technique to treat the fundamental cause of severe human disorders. In the last 4 years, these editing technologies have evolved and extended rapidly, with quick developments in their design to boost the underlying efficiency, targetability, and specificity. However, numerous obstacles must be overcome before the full potential of this platform may be achieved. Base-editing technologies are still in their infancy, and further in vivo characterization of these GET’s required to enable therapeutic applications. Much more study is required to describe and enhance base- editing and prime-editing in a variety of cell types and species. Cas9 and BE off-target impacts may differ, and a distinct evaluation technique is required to adequately analyze off-target editing across the genome. CBEs, in particular, produce more indels, off-target editing, and unwanted changes than ABEs (Zuo et al. 2019), while we anticipate that such restrictions will be reduced by more CBE engineering efforts. Whole-genome sequencing of human iPSCs stably expressing an evolved CBE, for example, revealed C-to-T and C-to-G mutations outside of the off-target locations predicted in silico. The bulk of off-target mutations were C: G→T: A transitions or C: G→G: C transversions that were selected for the APOBEC mutagenesis signature (Eisenberg et al. 2019). Prime editing appears to be associated with decreased off-target mutagenesis in human cell lines compared to base editing. Nonetheless, due to reverse-transcriptase-mediated extension beyond the primer sequence, prime editing might potentially produce tiny insertions at the target location. Furthermore, while Anzalone and colleagues found no variations in survival and very minor modifications in the cellular transcriptome of cell lines harboring inactivated RT, the clinical viability and safety of in vivo prime editing remain unknown (Tikhonova et al. 2019). Finally, whereas Cas engineering has broadened the breadth of BEs and PEs, not all gene editing reagents are made equal, and further work is needed to expand the variety of targetable PAM sites. Many of the new versions are less efficient than the original BEs created using nSpCas9. More Cas9 protein evolution and the discovery of novel nucleases would widen the spectrum of genome targeting while preserving editing efficiency and selectivity (Kantor et al. 2020).
16.4 Transcription Activator-Like Effector Nuclease (TALEN) TALENs proteins, which come from the phytopathogenic bacterium species Xanthomonas, were originally discovered in 2009 (Boch et al. 2009). A unique group of proteins called TALE may bind DNA. Due to its compatibility with a wide range of functional domains, TALEs provide versatile applications in genetic engineering. TALE proteins may change from transcriptional modulators to genome editing tools via various connections with transcriptional activators, repressors, or endonucleases (Thakore and Gersbach 2016). The TALEN system was chosen by
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Nature Methods as the tool of the year in 2011 (Nemudryi et al. 2014) because of its excellent specificity and accuracy in genome engineering, which make it an effective tool. A typical TALEN unit consists of an acidic domain for activating target gene transcription, a nuclear localization signal (NLS), a core DNA-binding domain with 1228 repetitions, and Fok1 nuclease (Nemudryi et al. 2014). The sequence of 33–35 largely consistent amino acids, together with polymorphic 12 and 13 repeat variable di-residues (RVDs), makes up the DNA-interacting region. Each repetition specifically binds to a single nucleotide on the target that is oriented 5′–3′ (Boch et al. 2011). According to biochemical structure-function investigations, the amino acid at position 13 uniquely identifies a nucleotide on the main groove of the DNA target (Stella et al. 2013; Deng et al. 2012). The amino acid at position 12 serves to stabilize this DNA-protein interaction unit. Only 20 amino acids make up the half repeat that binds the DNA sequence at the 3′-end of the target locus. The four most prevalent RVDs discovered via multiple experimental validations are NN, NG, HD, and NI, each of which bestows target specificity by its distinct preferred binding affinity for G/A, T, C, and A, respectively (Mussolino and Cathomen 2012). The screening of all 400 conceivable RVD combinations, which are thought to be non-conventional RVDs due to their rarity in nature (Miller et al. 2015), is also described (Juillerat et al. 2015). TALE proteins’ DNA binding domains (DBDs) are divided into two parts and are part of the widely utilized TALEN system. A Folk1 restriction enzyme’s catalytic domain is joined to each unit. The TALENs’ Fok1 nuclease dimerizes, creating a cleavage on both strands of DNA’s double helix and triggering the DNA repair system to heal the break. Repeat modules (RVDs) may be aligned in a certain structure to enable the creation of TALENS with the necessary sequence accuracy. However, the number of potential target locations for TALEN has a limit. It is always necessary to have thymine at position 0, or immediately before the TALE-repeat bound sequences (Mak et al. 2012). The weak van der Waal forces between the C5 methyl group of thymine and the highly conserved tryptophan in the N-terminal enable full gene activation. There are other reports of more recent TALEs in nature that function normally despite having cytosine in place of thymine at position 0. These scaffolds work without the necessary 5′T (Lamb et al. 2013). However, tailoring TALE-based methods to change any genome is both easy and extremely adaptable. According to the crystal structure of TALE proteins attached to target DNA, each repeating unit produces a V-shaped structure with two assembled alpha helix that is wrapped around the main groove of DNA using the hypervariable 12 and 13 amino acids (Mak et al. 2012).
16.5 Conclusion In conclusion, NDs present a significant global health challenge, affecting millions of individuals worldwide. The lack of precise diagnostic tools and effective treatments has fueled the urgent need for innovative approaches to combat these debilitating conditions. The emerging field of gene editing has opened up new doors of
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hope in the fight against NDs. Using GETs such as CRISPR-Cas9 and ZFNs, researchers can now target and modify specific genes associated with neurodegeneration. By addressing critical factors involved in NDs, including altered autophagy, signaling dysregulation, oxidative stress, mitochondrial dysfunction, and impaired neurotrophins and cytokines, GETs can correct genetic abnormalities and restore lost neural function. Moreover, integrating GETs with SCT presents a powerful combination that could revolutionize our understanding of human genetics and pave the way for regenerative medicine. The evolution and methodology of GETs have shown tremendous promise, enabling scientists to gain insights into the molecular mechanisms underlying NDs. With further advancements, these tools hold the potential to provide preventive and more targeted strategies against NDs. However, it is important to proceed with caution and address ethical considerations and safety concerns associated with gene editing. In summary, gene editing tools for NDs represent a beacon of hope in the quest for effective treatments and potential cures. The comprehensive overview provided in this chapter sheds light on the current understanding of NDs, the application of GETs, and the potential they hold to reshape the landscape of neurodegenerative disease research. By harnessing the power of gene editing, we may be one step closer to unraveling the mysteries of NDs and improving the lives of those affected by these devastating conditions.
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Lumbar Disc Disease: An Overview
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Shivani Patel, Santhana Kumar, Arun Soni, Sanjeev Acharya, and Niyati Acharya
Abstract
Lumbar disc syndrome (LDS) is a state that influences the intervertebral discs in the lower spine, lead to affliction, lack of sensation, and frailty in the lower back, legs, and feet. LDS is a condition that can result from bulging, protruding, extruding, or sequestered discs in the lower back. LDS comes in a variety of forms, including those caused by bulging and ruptured discs. A herniated disc, on the other hand, happens when the interior, gel-like elements of the disc spill out and pressure the vertebrae or nerves. The pathophysiology of LDS involves a change in the vertebral endplate, causing a loss of disc nutrition and disc degeneration. Deteriorating, apoptosis, abnormalities in collagen, vascular ingrowth, loads, and genetics have all been implicated in the pathophysiology of lumbar disc degeneration (LDD). Numerous factors, such as aging-related degeneration due to injuries to the spine, bad posture, weight gain, and inheritance, can be linked to the cause of LDS. Low backache, leg discomfort, sensations of numbness or tingling in the lower extremities S. Patel · S. Kumar Department of Pharmacology, SSR College of Pharmacy, Silvassa, Union Territory of Dadra and Nagar Haveli and Daman Diu, India A. Soni Anand College of Pharmacy, Anand, Gujarat, India S. Acharya Institute of Pharmacy, Ganpat University, Mehsana, Gujarat, India Department of Pharmacognosy, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India N. Acharya (*) Department of Pharmacognosy, Faculty of Pharmacy, Nirma University, Ahmedabad, Gujarat, India e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 A. Khan et al. (eds.), Mechanism and Genetic Susceptibility of Neurological Disorders, https://doi.org/10.1007/978-981-99-9404-5_17
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or feet, weaknesses, and trouble walking or standing are some of the signs of LDS. Diagnosis of LDS typically involves imaging tests such as X-rays, MRI, or CT scans to visualize the herniated or bulging discs and assess the extent of nerve compression. Spinal injections, such as epidural steroid injections, can provide relief by reducing inflammation and pain. Treatment options for LDS range from conservative therapies to surgical intervention, depending on the severity of symptoms and individual patient factors. Surgery may be necessary in some cases to relieve pressure on the affected nerves. Keywords
Propionibacterium acnes · Myelography · Ruptured disc · Spondylosis · Bulging disc
Abbreviations CT scans Computer tomography scans EMG Electromyography ILA Interlaminar approach LDH Lumbar disc herniate LDS Lumbar disc syndrome MG Myelography MRI Magnetic resonance imaging NSAIDS Nonsteroidal anti-inflammatory drugs OD Open discectomy P. acnes Propionibacterium acnes X-rays X-radiation
17.1 Introduction Lumbar Disc Syndrome (LDS), also known as degenerative disc disease, is a condition that affects the intervertebral disc in the lower back. The condition is characterized by the compression of nerves in the lower back due to disc pathology. LDS is a complex condition influenced by numerous factors. It can be managed through non-operative or operative treatments, depending on the severity and individual patient characteristics. LDS, also known as lumbar disc herniation (LDH), is the gesticulation of the lumbar disc’s fluid (the pulpous nucleus) along its outside (the fibrous ring), typically occurs in the posterior region and is the hallmark of LDH (Oliveira et al. 2014). The disc is a structure that acts as a cushions between the vertebrae, and they can degenerate over time. LDS is a frequent source of low back pain, and it can result from bulging, protruding, extruding, or sequestered disc (Goo et al. 2018). Among lower back neurodegenerative disorders, a herniated disc is the diagnosis that is more frequently made and the major justification for spinal surgery. Transdermic abscission was replaced by the conventional method, which was used in conjunction with microsurgical, endoscopic, and percutaneous procedures.
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The treatment for this ailment has advanced from superstition to endoscopic or minimally invasive procedures, even though it has been difficult to diagnose. Nonsurgical treatment options for LDH include the use of lower spine support, relaxation, oral medications or muscle relaxants, craniosacral therapy, physical activity rehabilitation, intramuscular NSAIDS, and behavioral therapy. The knowledge based on this condition exhibits both considerable accomplishments and areas of limited understanding (Unlu et al. 2008). The most typical diagnostic finding in the lumbar region of deteriorating illnesses, ruptured discs are the main cause of spinal surgery. Thus, comprehensive knowledge of LDH, its causative factors, and therapeutic approaches remains predominant (Kim et al. 2023a). Pads among the bones of the spine are provided by the discs that separate the vertebrae, aiding in shock absorption during motion. When a disc becomes impaired or ruptured, it can exert compulsion on spinal nerves, leading to a sensation of pain, numbness, and muscle weakness in the lower back and legs (Remotti et al. 2023). LDS often develops due to degenerative changes in the discs attributed to factors such as aging, harm, or too much lower back strain. Additionally, those who participate in strenuous physical activity, spend an excessive amount of time sitting down, or have sedentary lifestyles are more probable to develop it (Zale and Mitsunaga 2023). According to the extent of the rupture and the position of the afflicted disc, intervertebral disc syndrome indications can change. Lower pain in the back, pain in the legs, feeling numb, muscle weakness, and trouble moving about or standing are common side effects. Sciatica, a disorder that involves discomfort that spreads down the back of the leg and into the foot, can also be brought on by a herniated disc (Koes et al. 2007) (Fig. 17.1).
17.2 History Although the term “lumbar disc syndrome” is a more recent medical term, intervertebral disc-related problems have been understood since ancient times. Writings from ancient Egypt, Greece, and Rome, as well as other cultures, contain accounts Fig. 17.1 Lumbar disc syndrome
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of back pain and symptoms that may be associated with spinal problems. The “Father of Medicine,” Hippocrates, recorded incidents of back discomfort and spinal issues in his works.
17.2.1 Introduction of Disc Herniation Concept In the middle of the twentieth century, the idea of intervertebral disc herniation attracted a lot of interest. Two American doctors named William Jason Mixter and Joseph S. Barr wrote a seminal study in 1934 titled “Rupture of the Intervertebral Disc with Involvement of the Spinal Canal.” This study discussed the connection between sciatic nerve discomfort and ruptured discs. The work of Mixter and Barr was essential in highlighting how disc herniation contributes to neurological symptoms (Takada et al. 2001). 1. The key findings of the study (Gomleksiz et al. 2012): (a) They provided case studies of a number of patients who had sciatic nerve pain (pain radiating down the leg) that was severe and brought on by the compression of nerve roots in the lumbar spine. (b) They discovered the existence of herniated intervertebral disc material, notably in the lumbar area, using X-ray scans. They saw that neurological symptoms were being brought on by the herniated debris pressing against the spinal nerves. (c) The surgeons reported successful outcomes in terms of pain alleviation and functional improvement for their patients after performing surgical operations to remove the herniated disc material. 2. Significance of the study (Yuan et al. 2022): (a) Identification of a new pathology: The study made the medical community aware of the possibility that ruptured intervertebral discs are to blame for severe and incapacitating leg and back pain, especially sciatica, which transmits agony down the sciatic nerve’s course. (b) Change in perspective: Before their work, a lot of back pain cases and the symptoms they brought on were attributed to muscle strain or other general reasons. As a result of Mixter and Barr’s observations, the structural issue affecting the spinal discs and nerves became the preferred explanation for these symptoms. (c) Effect on therapy: The potential advantages of surgical intervention for some disc herniation instances were underlined in the paper. Although surgical intervention has previously been utilized to address spine-related conditions, their work revealed a clear link between herniation and surgical intervention. (d) Research foundation: Mixter and Barr’s publication provided the framework for future investigation into the pathophysiology, degeneration, and herniation of intervertebral discs. Researchers and medical professionals are becoming increasingly interested in spinal problems as a result of this work.
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The discipline of spinal medicine saw a paradigm shift as a result of Mixter and Barr’s seminal publication. Their findings laid the basis for later LDH studies, diagnostic methods, and treatment approaches. In order to effectively target treatment strategies, the understanding of spinal problems has progressed from general, nonspecific terminology to a more detailed anatomical basis. Overall, Mixter and Barr’s work significantly influenced how medical practitioners see and treat LDH, which eventually improved patient care and results. Medical professionals and anatomists started looking into the physiology and function of the spine, including discs, between the vertebrae in the nineteenth century. The first surgical options for ruptured discs were created in the early twentieth century, and in the middle of the century, the adoption of technological advances in imaging like X-rays and MRI scans enabled to detect slipped discs more precisely (Matsuo et al. 2023).
17.2.2 Advancements in Surgical Treatment Surgical methods for treating severe herniated disc patients were created as our knowledge of lumbar disc condition expanded. The development of microsurgical procedures in the second half of the twentieth century made it possible to remove herniated disc material more precisely while causing less harm to the tissues around it. For many patients, this development resulted in better outcomes and quicker recoveries (Junior et al. 2022).
17.2.3 Non-Surgical Treatment Approaches Non-surgical management strategies for lumbar disc dysfunction have grown in popularity over time. The problem was treated with physiotherapy, chiropractic adjustments, epidural steroid injections, and pain relief methods. These methods sought to enhance patients’ quality of life while reducing pain and inflammation without using surgery (Dea et al. 2020).
17.2.4 Holistic Management and Practice A change toward a more comprehensive strategy for spinal health has occurred in recent years. This method places a strong emphasis on not only addressing immediate symptoms but also encouraging general spine health through dietary changes, physical activity, and good posture. Preventive treatments are now thought to be crucial for lowering the incidence of LDS and associated problems. These include maintaining a healthy weight, using excellent ergonomics, and staying physically active (Brox et al. 2010). After that, numerous developments in the medical management of LDS have been made, including the use of less-invasive surgical procedures, physical therapy, and painkillers. Currently, LDS is acknowledged and
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successfully treated by medical specialists, and still further research is being made for the management of the disease in the development of even more potent medicines (Lincoln et al. 2002).
17.3 Epidemiology of LDS There are many people who suffer from LDS, which affects a sizable section of the population. Its prevalence rises with age and is higher in those between the ages of 30 and 50. Although some research indicates a higher prevalence in men, the syndrome impacts equally people. The probability of acquiring the syndrome can be influenced by elements like genetics, profession, and lifestyle (Walter et al. 2023). Four hundred million people worldwide are anticipated to be diagnosed with pathologic disc degeneration each year, or about 5.5% of the world’s population. On MRI scans, 58.6% of younger patients with symptoms showed signs of LDD. Age was a factor in the overall prevalence of confirmed spinal degenerative diseases, including disc disease, which was 27.3%. Based on MRI scans, it was discovered that 58.6% of symptomatic younger patients had LDD. Over 90% of people over the age of 50 have disc degeneration over their entire spine, compared to 71% of men and 77% of women in this age group. At least 30% of adults between the ages of 30 and 50 are predicted to have some degree of disc space degeneration, while not everyone will experience pain or obtain a formal diagnosis (Burke 2001).
17.4 Anatomy of the Lumbar Disc Syndrome The five vertebrae (L1–L5) that make up the lumbar spine are stacked on top of one another. The intervertebral discs between adjacent vertebrae provide flexibility and allow the spine to move by acting as shock absorbers. The nucleus pulposus, a gel- like interior of these discs, is encircled by the annulus fibrosus, a thick, fibrous outer layer (Borenstein et al. 2001). The spine is flexible and can move because of the intervertebral discs, which act as cushions and shock absorbers between adjacent vertebrae. The nucleus pulposus, which is a gel-like substance, and the fibrous annulus fibrosus, which surrounds the nucleus, are the two primary parts of these discs (Borenstein et al. 2001).
17.4.1 Understanding the Anatomy in Normal Conditions The intervertebral discs typically have a healthy nucleus pulposus, and an intact annulus fibrosus, and are well-hydrated in those who do not have LDS. The discs support the spine during motion and weight-bearing activities while maintaining their structural integrity. Strong and able to endure the forces applied to it, the annulus fibrosus (Cassinelli et al. 2001).
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17.5 Pathophysiology of LDS The deterioration of intervertebral discs and the possibility for disc material to herniate can have a substantial impact on the architecture of the lumbar spine in populations with LDS and is a series of intricate processes within the spine (Kritschil et al. 2022). The following alterations could be seen:
17.5.1 Disc Degeneration The water content and flexibility of the intervertebral discs may decrease over time. The annulus fibrosus may become weaker as a result of this deterioration, making it more prone to rips and herniation (Taniguchi et al. 2023). 1. Loss of water content: The typically hydrated nucleus pulposus gradually loses water over time as a result of age or other circumstances. As a result, it is less useful as a shock absorber (Mohd Isa et al. 2022). 2. Loss of elasticity: As a result of degeneration, the discs’ elasticity may decline, making them less resilient to mechanical stress and movement (Holm 1993). 3. Annulus fibrosus changes: Changes to the fibrous annulus fibrosus that surrounds the nucleus pulposus include thinning, weakening, and increased susceptibility to tearing. The nucleus pulposus may herniate as a result of these holes (Martin et al. 2002).
17.5.2 Nucleus Pulposus Herniation In people with LDS, the annulus fibrosus may be torn or weak, allowing the nucleus pulposus to protrude. The spinal cord or surrounding spinal nerves may become compressed as a result of this herniation, resulting in pain and other neurological symptoms (Choi 2009). 1. Localized or radiating pain might be brought on by herniated discs: When the sciatic nerve is injured, the pain frequently follows the path of the damaged nerve, which is referred to as “sciatica” in common usage (Zhao et al. 2019). 2. Numbness alongside tingling: Along the neural pathway, nerve compression can cause sensations such as tingling, numbness, or “pins and needles” feelings (Manchikanti et al. 2009). 3. Muscle weakness: In the regions where the afflicted nerves are innervated, chronic nerve compression can cause muscle weakness. The movement and daily activities may be impacted by this impairment (Williams and Christo 2009).
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17.5.3 Nerve Compression Compression of the spinal nerves can occur as a result of the herniated disc material, which can cause a variety of symptoms, including localized or radiating pain, numbness, tingling, and muscle weakness. The particular symptoms felt depend on the extent and location of the herniation (Michopoulou 2011). 1. Inflammation: Herniated disc material along with nerve compression may cause an inflammatory reaction to occur in the affected area, which can increase pain and discomfort (Centeno et al. 2017). 2. Inflammation and disc degeneration: People with LDS experience immunological and inflammatory responses when their intervertebral discs deteriorate and herniate. Even though it is a normal defense mechanism, inflammation in the setting of LDS can increase pain and speed up the onset of symptoms (Roh et al. 2021). 3. Local inflammatory mediators: Damaged or herniated disc material may release cytokines, chemokines, and prostaglandins, among other inflammatory mediators. These signaling molecules entice immune cells and support a heightened inflammatory response locally (Khan et al. 2017). 4. Sensitization and irritation of spinal nerves: As inflammatory mediators build-up surrounding the herniated disc debris, they may irritate and sensitize neighboring spinal nerves. This inflammation may intensify pain signals and exacerbate the discomfort felt by those with LDS (Deyab 2019). 5. Vasodilation, which is brought on by inflammation, causes an increase in blood flow to the affected area. Although increased blood flow is a necessary component of the body’s healing process, it can also cause swelling, which exacerbates pain and discomfort (Kompel 2008). 6. Nociceptor sensitization: Pain receptors called nociceptors are present in all of the body’s nerves. These nociceptors may become sensitized by inflammation, making them more sensitive to stimuli. Because of this, even slight pressure or movement might cause intensified pain feelings (Wang et al. 2020). 7. Contribution to pain: The severity of symptoms and perception of pain in LDS can both be strongly influenced by the inflammatory response (Bezerra et al. 2021).
17.5.4 Changes in Structure In more serious cases, recurrent compression together with degeneration can cause changes in the structure of the afflicted discs and surrounding vertebrae. This might exacerbate instability and have an impact on the spine’s general biomechanics. 1. Bulging discs: The pressure from the herniated material can cause discs to bulge outward, changing the contour that covers the intervertebral space. 2. Reduced disc height: Disc degeneration can cause a decrease in disc height, which may alter the distance between adjacent vertebrae and the spine’s stability.
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Individuals with LDS experience structural changes in the lumbar spine, including disc degeneration, herniation, bulging, facet joint modifications, and muscle imbalances. Pain, nerve compression, and restricted mobility are just a few of the symptoms brought on by these alterations taken as a whole. Accurate diagnosis and the creation of management plans that are suited to each person’s particular needs depend on an understanding of these fundamental changes.
17.6 The Genetic Susceptibility Associated with LDS The disc’s durability and strength during compression can be affected by changes in the DNA sequences that codify for fibro alongside other structural protein molecules. The disc’s capacity to endure mechanical stress and respond to changes due to aging can be influenced by inheritance (Hertzman-Miller et al. 2002). 1. Collagen composition: The extracellular matrix, or outer layer, of the disc that connects the vertebrae, which is primarily made up of the protein collagen, is affected by mutations in genes that can have an impact on the spine’s integrity. The discs may be extra susceptible to degradation due to irregular elastin structure (Murad et al. 2022). 2. Matrix metalloproteinases (MMPs): MMPs, catalysts involved in structural remodeling, can be produced in response to inherited traits. By destroying elastin along with additional building blocks, improper functioning of MMPs may lead to the deterioration of discs (Rodrigues Bento et al. 2022). 3. Cytokines and inflammation: The generation of inflammatory substances, messenger molecules that trigger immune system responses, can be affected by genetic differences. Chronic disc inflammation brought on by changes in the production of cytokines may hasten degenerative changes in the disc (Isselbacher et al. 2016). 4. Vitamin D receptor: A variation in the vitamin D receptor gene’s genetic mutations may have been connected to degenerative discs. Vitamin D controls cellular functions and affects swelling, contributing to the maintenance of spine health (Fry et al. 2007). 5. Aggrecan and disc proteins: The capability of the spine to preserve moisture and withstand physical strain can be impacted by genetic variations in the genes encoding aggrecan that help along with additional disc proteins (Fuller et al. 2016). 6. Pain perception and sensitivity: An individual’s sense of tenderness brought on by lumbar disc disease may vary depending on inherent aspects of sensation of pain, neuron modulation, and neuronal hypersensitivity (Zhu 2009).
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Fig. 17.2 Spinal disc herniation
17.7 Types of LDS Although there is not a rigid method of classification for various varieties of LDS, the condition can be divided based on the unique traits and elements that contribute to the symptoms. Here are some broad categories for describing many LDS facets:
17.7.1 Lumbar Disc Herniation A LDH, also known as a “slipped disc” or a “herniated disc,” is a disorder in which the inner core of a spinal disc pushes through the outer layer. As a result, the lower back (lumbar region) and other areas of the body, including the legs, may experience discomfort, numbness, or weakness. This can also put a strain on surrounding nerves. The vertebral discs, which soften the spaces between the individual vertebrae in the spine, are soft, rubbery cushions. They are composed of a strong outer layer called the annulus fibrosus and an inner core that resembles gel (Fig. 17.2). A piece of the nucleus pulposus will often protrude through a tear or weak spot in the annulus fibrosus to cause a herniated disc. Numerous symptoms may result from this protrusion’s irritation or compression of surrounding spinal nerves (Al Qaraghli and De Jesus 2023). LDH includes some common symptoms: 1. Low back pain: This type of pain can be localized to the lower back or can radiate down the leg (sciatica). It can be mild to severe. 2. Sciatica: Sciatica is a term used to describe discomfort that spreads down the sciatic nerve’s course, which runs from the lower back to the buttocks and legs. It may result in leg pain, tingling, and numbness. 3. Numbness and tingling: These sensations can occur in the buttocks, legs, and feet due to nerve compression. 4. Muscle weakness: It is possible to experience weakness in the legs, buttocks, and lower back, which can make it difficult to move or carry out daily tasks. 5. Changes in reflexes: Reflexes in the afflicted leg could be reduced or different. 6. Pain exacerbated by certain activities: Sitting, standing, bending, lifting, or sneezing may make the pain worse.
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17.7.2 Lumbar Disc Degeneration LDD is a condition where the spinal discs located in the lower back gradually break down over time, leading to pain and stiffness in the back. The degeneration can cause various changes in the structure of the discs, including disc bulging, osteophytes, loss of disc space, and compression and irritation of the adjacent nerve root (Donnally III et al. 2023; Wu and Cruz 2023). Here are some key points about LDD: 1. Lumbar disc degeneration is a common condition that affects many people as they age. 2. Risk factors for developing disc changes include older age, obesity, lack of exercise, and lifting heavy loads. 3. Despite what the name suggests, degenerative disc disease is neither considered a true disease nor does it progressively worsen with time. Discs naturally stiffen with use and age, and everyone experiences some disc degeneration.
17.7.3 Lumbar Radiculopathy (Lee et al. 2020) Lumbar radiculopathy, also known as sciatica, can be associated with lumbar disc diseases such as a herniated disc, degenerative disc disease, or stenosis of the lumbar spine. However, it is important to note that not all cases of lumbar radiculopathy are caused by disc diseases, as other factors like spinal stenosis or nerve root injuries can also contribute to its development. Lumbar radiculopathy is characterized by radiating leg pain, abnormal sensations, and muscle weakness due to compression or inflammation of a spinal nerve root in the lower back. The specific areas of the leg and foot that are affected depend on which nerve in the low back is affected.
17.7.4 Lumbar Stenosis (Woodfield et al. 2023; Liyew 2020) Lumbar stenosis is a type of lumbar disease that refers to the narrowing of the spinal canal in the lower back, which can compress the nerves traveling through the lower back into the legs. Lumbar stenosis can be caused by numerous factors, including degenerative changes of the spine, such as osteoarthritis, herniated discs, or thickened ligaments. Here are some key points about lumbar stenosis: 1. Lumbar stenosis is a common cause of low back and leg pain, or sciatica. 2. Symptoms of lumbar stenosis may include pain in the back, burning pain going into the buttocks and down into the legs, numbness, tingling, cramping, or weakness in the legs, and loss of sensation in the feet. 3. Lumbar stenosis can be associated with other lumbar diseases, such as herniated discs, degenerative disc disease, or stenosis, of the lumbar spine.
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17.7.5 Cauda Equina Syndrome Cauda equina syndrome is a type of lumbar disease that affects the bundle of nerve roots at the lower end of the spinal cord. It is a rare but serious condition that can cause extreme pressure and swelling of the nerves, leading to symptoms such as low back pain, pain that radiates down the leg, numbness around the anus, and loss of bowel or bladder control. Cauda equina syndrome can be caused by numerous factors, including a herniated disc, spinal stenosis, spinal tumors, infections, or trauma (Bonfioli et al. 2023).
17.7.6 Bulging Disc It occurs when the inner portion of the intervertebral disc begins to protrude from the outer wall of the disc but does not actually tear. A bulging disc, also known as a disc protrusion or disc bulge, is a spinal condition in which the inner core of a vertebral disc pushes against the outer layer without actually rupturing it. This can cause the disc to protrude beyond its normal boundaries and potentially put pressure on nearby spinal nerves. While similar to a herniated disc, a bulging disc involves a different mechanism and typically presents with milder symptoms (Dietz 1993). A bulging disc occurs when the inner core (nucleus pulposus) of a vertebral disc pushes against the outer layer (annulus fibrosus) due to age-related wear and tear, injury, or other factors. Unlike a herniated disc, where the outer layer tears, a bulging disc retains its outer covering. The symptoms of a bulging disc can vary widely. Some people may experience no symptoms at all, while others might have mild-to- moderate back pain, stiffness, or discomfort. If the bulging disc compresses a nearby nerve, it can lead to radiating pain, numbness, tingling, or weakness in the limbs. The severity of symptoms depends on the location of the bulging disc and the extent of nerve compression (Table 17.1).
17.8 Etiology of LDS LDS has a complex multifactorial etiology that combines genetic, environmental, and mechanical elements. The following are some important causes:
17.8.1 Genetics The make-up and structure of the intervertebral discs can be affected by genetic factors. The strength and flexibility of the discs can be impacted by variations in the genes that code for collagen, which serves as the backbone of the discs. How the body reacts to disc degeneration and injury may also be influenced by genetic variations in genes related to inflammation. The genetic contribution to disc herniation is
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Table 17.1 Types of lumbar disc syndrome Sr. no Types 1. Lumbar disc herniation: A lumbar disc herniation, also known as a “slipped disc” or a “herniated disc,” is a disorder in which the inner core of a spinal disc pushes through the outer layer. The vertebral discs, which soften the spaces between the individual vertebrae in the spine, are soft, rubbery cushions. A piece of the nucleus pulposus will often protrude through a tear or weak spot in the annulus fibrosus to cause a herniated disc. 2. Lumbar disc degeneration: Lumbar disc degeneration is a condition where the spinal discs located in the lower back gradually break down over time, leading to pain and stiffness in the back. The degeneration can cause various changes in the structure of the discs, including disc bulging, osteophytes, loss of disc space, and compression and irritation of the adjacent nerve root. 3. Lumbar radiculopathy: Also known as sciatica, can be associated with lumbar disc diseases such as a herniated disc, degenerative disc disease, or stenosis of the lumbar spine. Important to note that not all cases of lumbar radiculopathy are caused by disc diseases, as other factors like spinal stenosis or nerve root injuries can also contribute to its development. 4.
Lumbar stenosis: It is a type of lumbar disease that refers to the narrowing of the spinal canal in the lower back, which can compress the nerves traveling through the lower back into the legs. It is caused by numerous factors, including degenerative changes of the spine, such as osteoarthritis, herniated discs, or thickened ligaments.
Key point The lower back (lumbar region) and other areas of the body, including the legs, may experience discomfort, numbness, or weakness, pain exacerbated by certain activities.
References Al Qaraghli and De Jesus (2023)
It is a common condition that affects many people as they age. Risk factors for developing disc changes include older age, obesity, lack of exercise, and lifting heavy loads.
Donnally III et al. (2023), Wu and Cruz (2023)
It is characterized by radiating leg pain, abnormal sensations, and muscle weakness due to compression or inflammation of a spinal nerve root in the lower back. The specific areas of the leg and foot that are affected depend on which nerve in the low back is affected. Common cause of low back and leg pain, or sciatica. Symptoms of lumbar stenosis may include pain in the back, burning pain going into the buttocks and down into the legs, numbness, tingling, cramping, or weakness in the legs, and loss of sensation in the feet.
Lee et al. (2020)
Woodfield et al. (2023), Liyew (2020)
(continued)
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Table 17.1 (continued) Sr. no Types 5. Cauda equina syndrome: Syndrome is a type of lumbar disease that affects the bundle of nerve roots at the lower end of the spinal cord. Cauda equina syndrome can be caused by numerous factors, including a herniated disc, spinal stenosis, spinal tumors, infections, or trauma.
6.
Bulging disc: It occurs when the inner portion of the intervertebral disc begins to protrude from the outer wall of the disc but does not actually tear. Also known as a disc protrusion or disc bulge, is a spinal condition in which the inner core of a vertebral disc pushes against the outer layer without actually rupturing it. This can cause the disc to protrude beyond its normal boundaries and potentially put pressure on nearby spinal nerves.
Key point It is a rare but serious condition that can cause extreme pressure and swelling of the nerves, leading to symptoms such as low back pain, pain that radiates down the leg, numbness around the anus, and loss of bowel or bladder control. It occurs when the inner core (nucleus pulposus) of a vertebral disc push against the outer layer (annulus fibrosis) due to age-related wear and tear, injury, or other factors. Causes mild back pain, stiffness, and discomfort.
References Bonfioli et al. (2023)
Dietz (1993)
complicated, and the precise genes involved have not yet been fully identified (Samuel and Radovanovic 2019). 1. COL9A2 and COL9A3 genes: Those alleles’ modifications, which produce elastin molecules, were linked to a greater probability of spinal degeneration. The rigidity of the spine may be weakened by a changed elastin component (Saper et al. 2019). 2. ADAMTS genes: These transcripts produce the chemical reactions necessary to degrade specific matrix-associated molecules. Protein production and degradation may be balanced differently according to hereditary variances, which might have an effect on disc stability (Poon et al. 2004). 3. IL-1 and IL-6 genes: Interleukin-1, also known as IL-1, & IL-6 genetic variations can influence the response to inflammation in the disc. Increasing amounts of those mediators may speed up deterioration (Egea et al. 2020). 4. Vitamin D receptor gene: The immune system’s response to sunlight, or vitamin D, which particularly is important to sustaining disc condition and controlling inflammatory processes, can be affected by inherited changes in this chromosome (Burr 2020). 5. Aggrecan gene: A crucial protein peptide in the outermost layer of the vertebrae is aggrecan. The manufacturing process and its disc’s capacity to hold liquid may be impacted by variations in DNA (Chen et al. 2023).
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6. GDF5 gene: These gene’s polymorphisms have been found to be linked to degenerative disc disease. The gene involved might have an impact on disc stability since it controls the activities of cells (Capoor et al. 2019).
17.8.2 Propionibacterium acnes Propionibacterium acnes (P. acnes) has been connected to the emergence of low back discomfort, also referred to as spinal disc dysfunction, which is also referred to a novel discovery that contributes as a contributive factor for LDS. P. acnes has been associated with low back pain and has been found in disc material from patients with LDH. P. acnes has been shown to induce accelerating nuclei pulposus cell death through the TLR2/JNK/mitochondrial-mediated mechanism to cause the degeneration of intervertebral discs (Guo et al. 2023).
17.8.3 Acidic Environment The presence of acids within the intervertebral discs, are also a causative agent for LDS. The nucleus pulposus (the gel-like center of the discs) becomes more acidic as the discs deteriorate and damage (Yang et al. 2022). When such an acidic environment prevails, it causes the extracellular matrix to breakdown, which thereby leads to disc degeneration. It is also responsible for the growth of harmful bacteria such as P acnes, because of the favorable environment, leading to the development of Discitis and LDS. LDS indications may develop because of this. The discs’ acidity may also foster the growth of dangerous bacteria like Propionibacterium acnes, which may encourage the emergence of discitis and LDS (Kim et al. 2023b).
17.8.4 Spondylosis Spondylosis is a term used to describe degenerative conditions of the spine, particularly osteoarthritis of the spine. It is a usual situation that usually develops with age and is characterized by wear and tear on the spinal discs and bones. The condition can affect any part of the spine, but it is more frequently seen in the cervical (neck) and lumbar (low back) areas. Spondylosis can lead to lower the likelihood of generating an acidic atmosphere and prevent it from the spinal cord and nerve roots (Londhe et al. 2022). As the discs deteriorate, they may sustain damage that leads to loss of height and develop minute fissures or tears in their outer covering. The gel-like center of the disc may begin to seep out as a result, irritating nearby nerves and resulting in apathy, vulnerability, and lower back pain that travels down the legs are also present (Vialle et al. 2010).
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17.8.5 Spinge Stenosis Spinal stenosis is a state that occurs when the spaces in the spine narrow, causing pressure on the spinal cord and nerve roots. The pressure on the roots of the nerves caused by the constriction may result in pain or fatigue in the legs, back, and other areas. Several signs could result from this, such as leg, low back, and hip discomfort, sensations of ting vulnerability, and numbness (Virtanen et al. 2007).
17.8.6 Herniation of Nucleus Pulposus When the soft and gelatinous center of a disc between the vertebrae is squeezed through a weak spot in the disc, it causes back discomfort and irritation of the nerve roots. This disease is known as herniated nucleus pulposus (Hansen 1964). According to the precise position of the lesion and the level of nerve inflammation or bending, the signs and symptoms of a bulging nuclei pulposus can change (Dilke et al. 1973).
17.9 Risk Factors of LDS Several risk factors that can raise the possibility of developing the illness can influence it (Hahne et al. 2010; Byvaltsev et al. 2023). The main LDS risk factors are listed below: 1. Age: The discs in the spine naturally fluctuate as we become older. Less water is present in the discs, which results in less flexibility and shock absorption. Additionally, the discs lose their capacity to appropriately transfer stress along the spine. The chance of disc herniation is increased by these modifications, often known as disc degeneration. 2. Mechanical factors: Heavy lifting, bad posture, and repetitive motions can strain the intervertebral discs and hasten their deterioration. The lumbar spine is subjected to greater mechanical stress in certain jobs or activities that frequently require bending, twisting, and lifting, which raises the possibility of disc herniation. 3. Obesity: Extra body weight adds to the lumbar spine’s mechanical stress, which accelerates disc degeneration. Chronic low-grade inflammation that damages the discs and hastens their degeneration is linked to obesity. 4. Smoking: Smoking has been linked to a reduction in the discs’ blood flow. Reduced blood flow makes it difficult for the discs to get the nutrients and oxygen they need to heal and preserve their structural integrity. Smokers are more likely to experience disc herniation and degeneration. 5. Trauma: The annulus fibrosus may tear or rupture as a result of acute trauma, such as a violent blow or injury. This could happen in slip-and-fall or car accidents. The structural integrity of the disc is compromised by trauma, which
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allows the nucleus pulposus to protrude through the tear and cause herniation and nerve compression. 6. Sedentary lifestyle: Prolonged sitting and inactivity erode the spine’s supporting muscles. Weak muscles cannot support the spine’s natural curve in a way that is sufficient, which results in bad posture and uneven disc stress. 7. Incorrect lifting approach: Using the back to raise heavy objects instead of the legs puts too much pressure on the intervertebral discs. The discs are designed to withstand compressive forces rather than shear forces, which might be generated during incorrect lifting. 8. Degenerative changes: The discs lose water with time, which reduces their capacity to absorb trauma. The discs’ structural integrity is impacted by the water loss, making them more prone to bulging and herniation. 9. Genetic predisposition: Genetic variables affect how the discs react to inflammation and mechanical stress. Some people may inherit mutations in the genes that control inflammation or collagen formation, which increases their risk of disc degeneration. 10. Occupational vibration exposure: Long-term whole-body vibration exposure, like that endured by truck drivers or those operating large machinery, may raise the risk of disc degeneration and herniation. (a) Impact on spinal structures: Long-term vibration exposure can put the spine, notably the lumbar area, under mechanical stress and compression. The repeated vibrations might lead to increased pressure on the intervertebral discs, which serve as cushions between the vertebrae. (b) Disc degeneration: Over time, exposure to occupational vibrations may hasten the degeneration of the intervertebral discs. The structural integrity of the discs is weakened by disc degeneration, which increases the risk of herniation. (c) Acceleration of wear and tear: Vibrations can hasten the spine’s normal aging-related wear and tear. The cumulative effects of vibration exposure might cause the discs to prematurely age, increasing their susceptibility to herniation. (d) Frequency and intensity: The frequency and intensity of the vibrations can have an impact on the likelihood of developing LDS as a result of vibration exposure. Greater risk could be presented by longer periods of exposure to higher levels of vibration. Individuals can make preventive efforts to lower their risk of acquiring LDS by being aware of these risk factors. It is crucial to remember that, while these factors do play a part, a comprehensive strategy for spine health combines leading a healthy lifestyle, adopting excellent posture, being active, and getting the right medical attention when necessary.
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17.10 Management of LDS LDS is managed and treated with the goal of reducing pain, enhancing function, and improving overall quality of life for those who are affected. Depending on the patient’s unique situation and the degree of their symptoms, several approaches are taken (Hossain et al. 2023; Elsaka et al. 2022). Here is a thorough explanation of LDS management and treatment methods: 1. Conservative management: In many situations, LDS can be adequately controlled without undergoing surgery with the use of conservative treatments: (a) Rest: The body can mend and minimize inflammation when it gets enough sleep. However, protracted bed rest is typically not advised due to the risk of consequences such as muscle weakness. (b) Physical therapy: A well-organized physical therapy program concentrates on exercises that build core strength, increase flexibility, and reduce discomfort. Techniques to enhance posture and body mechanics are also included. (c) Painkillers: Nonsteroidal anti-inflammatory medicines (NSAIDs) sold over the counter or on prescription can be used to treat pain and lessen inflammation. (d) Steroid injections into the epidural space: These injections provide painkillers and anti-inflammatories right to the site of inflammation. (e) Application of heat or cold to the affected area can assist in relieving muscle tension and ease discomfort. (f) Bracing: In some circumstances, a brace or corset may be advised to offer extra support and lessen spinal strain. 2. Surgical intervention may be considered if conservative therapy is ineffective or if the symptoms are severe and long-lasting: (a) Discectomy: In a discectomy, the herniated section of the disc that is pressing on the spinal nerves is removed. The purpose of this surgery is to relieve nerve compression and the symptoms that go along with it. (b) Microdiscectomy: A tiny incision and specialized equipment are used in the minimally invasive microdiscectomy operation to remove the herniated disc material with the least amount of harm to the surrounding tissues. (c) Laminectomy: When there is severe nerve compression, the afflicted nerves may need to have a part of the spinal bone (the lamina) removed in order to get more room. (d) Spinal fusion: After a discectomy or laminectomy, spinal fusion may occasionally be advised to stabilize the spine. Adjacent vertebrae are fused in order to stop motion and lessen pain. 3. Lifestyle changes: Adopting a healthy lifestyle can help with every aspect of the management of LDS. (a) Sustain a healthy weight: Carrying too much weight strains the spine. Losing weight might lessen stress on the lumbar discs.
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(b) Consistent exercise: Low-impact activities like yoga, walking, and swimming can help build muscles, increase flexibility, and maintain the health of the spine. (c) Adequate body mechanics can help prevent further spinal injuries by teaching and practicing good lifting techniques, posture, and body mechanics. LDS is managed and treated using a combination of conservative techniques, such as rest, physical therapy, painkillers, and injections, as well as possible surgical treatments. In order to achieve the best results, a personalized strategy that considers the patient’s particular symptoms, condition severity, and general health is crucial. Healthcare practitioners can assist people with LDS to reclaim their quality of life by managing pain, boosting mobility, and improving the patient’s understanding of their disease.
17.11 Intervention of LDS (Wei et al. 2023; Alnafjan 2022) 1. Epidural nerve block: Similar to epidural steroid injections, epidural nerve blocks provide anesthetic drugs directly to the afflicted nerves to temporarily relieve pain. 2. Radiofrequency ablation (RFA): Long-lasting pain relief is provided by the radiofrequency ablation (RFA) procedure, which employs heat produced by radiofrequency radiation to specifically kill the nerve fibers that are responsible for the pain. 3. Minimally invasive surgery (MIS): Minimally invasive surgery (MIS) is a type of surgery that uses smaller incisions than traditional open surgery, which can lead to less damage to surrounding muscles and tissues, faster recovery times, and reduced infection and blood loss (Dittmar-Johnson et al. 2022). Surgeons can use MIS for other types of spine surgery, including laminectomy, spinal fusion, and lumbar disc arthroplasty (Watanabe et al. 2019). MIS can offer several benefits over traditional open surgery, including faster recovery times, reduced infection and blood loss, and less damage to surrounding muscles and tissues. 4. Interlaminar approach: The interlaminar approach is a minimally invasive surgical technique used to treat LDH and spinal stenosis. The technique involves making a small incision in the back and inserting an endoscope through the interlaminar space, which is the space between two adjacent vertebrae. The interlaminar approach can be performed using a variety of endoscopic tools and techniques, including full-endoscopic and percutaneous endoscopic approaches. The technique has been shown to be effective and minimally invasive, with low complication rates and faster recovery times compared to traditional open surgery. The technique has specific indications, such as highly migrated disc herniations, and is not suitable for all patients, particularly those with spinal instability or serious scoliosis (D’Antoni et al. 2022).
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17.12 Diagnostic Tools for LDS Effective care of LDS depends on a precise diagnosis. In order to assess the severity of disc degeneration, herniation, and nerve compression, healthcare practitioners employ a variety of diagnostic tools and techniques (Haskel et al. 2020; Bouthors et al. 2019). The main LDS diagnostic tools are listed below.
17.12.1 Medical History and Physical Exam The first stages in diagnosing LDS must include a thorough medical history and physical exam. 1. History: The medical professional asks the patient about their symptoms, pain patterns, medical background, and any previous back problems. 2. Physical examination: The healthcare professional evaluates muscular strength, reflexes, range of motion, and any indications of nerve compression, such as pain during specific motions.
17.12.2 Imaging Studies Imaging methods help diagnose disc degeneration, herniation, and nerve compression by giving visual insights into the lumbar spine. 1. X-rays: X-rays produce precise images of the bones that can be used to spot any structural irregularities, alignment problems, or degenerative symptoms like osteophyte formation or a reduction in disc space. 2. The intervertebral discs and spinal nerves can be seen in detail using magnetic resonance imaging (MRI), which is a potent technique. Herniated discs, nerve compression, and inflammation may all be visible. MRI is commonly used to evaluate the characterization, extent, and changes associated with degenerative lumbar disc disease. It provides detailed images of the intervertebral discs, allowing for the visualization of disc degeneration, herniation, and nerve compression. MRI is a valuable diagnostic technique in the evaluation of LDS. It provides detailed images of the lumbar spine, allowing for the visualization of disc degeneration, herniation, and nerve compression. MRI findings can help guide treatment decisions and assess the severity of disc degeneration (Jiang et al. 2022). 3. CT scan: CT scans produce cross-sectional images of the spine that make it possible to see the bones, discs, and other components. For evaluating bone structures and spotting fractures, they are especially helpful. CT is often used and available for the detection of morphologic changes in the spine, including herniated discs. It has a well-recognized role in the diagnosis of herniated discs (Akbari et al. 2021). IT can provide cross-sectional images aid-
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ing in the diagnosis of LDS. CT provides detailed images of the bony structures and can help visualize the extent of disc herniation and nerve compression. CT can be a valuable diagnostic tool in the evaluation of LDS. It is often used to identify and assess the morphologic changes associated with disc herniation. CT scans provide detailed cross-sectional images that can aid in the diagnosis and treatment planning for patients with LDS (Madhuchandra et al. 2023). 4. Myelography: A medical imaging method called myelography might be utilized to assess LDS. It entails inserting an instrument into the lower part of the back to do a puncture there, administering a substance that provides contrast into the vertebral column fluid, and then using X-rays or computed tomography (CT) scans to see the nerve roots and neurons (Shi et al. 2022). The precise position and severity of pressure on the nerves brought on by a bulging disc or other spinal problem can be determined with the aid of myelography. The contrast agent can assist in highlighting regions where a disc herniation or other abnormalities is compressing or displacing the spinal cord or nerves. This aids in deciding on the best course of action, including whether to do surgery or other procedures (Choi et al. 2023).
17.13 Prevention of LDS (Din et al. 2022; Tamagawa et al. 2022) Preventing LDS entails forming healthy routines and making lifestyle decisions that lower the chance of disc injury and degeneration. The danger cannot always be totally eliminated, but the following methods can lessen the possibility of getting LDS: 1. Maintain a healthy lifestyle weight: Carrying around extra pounds puts extra strain on the intervertebral discs and the spine. The risk of disc degeneration can be decreased by maintaining a healthy weight with a balanced diet and frequent exercise. 2. Maintain good posture: Maintaining good posture will assist in distributing weight more evenly across the spine and lessen pressure on the discs. This is true for sitting, standing, and lifting. When sitting for prolonged durations, use supportive pillows and ergonomic chairs. 3. Maintain physical activity: Exercise frequently to build the muscles that support the spine. Exercises like yoga, swimming, and walking help enhance the flexibility and health of the spine. 4. Use correct lifting techniques: To reduce stress on the discs, lift objects with your legs rather than your back. Keep the item near to your body while bending your knees. 5. Avoid smoking: Smoking limits the amount of blood that gets to the discs, which makes it harder for them to recover and keep their structure. Better spine health can result from quitting smoking. Pressure on the discs: When sitting for prolonged durations, use supportive pillows and ergonomic chairs.
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6. Exercises to strengthen your core: By strengthening the muscles in your core, especially your lower back and abdominals, you can better support your spine and minimize your risk of disc-related problems. 7. Exercise caution when repeating motions: Over time, repetitive bending, twisting, or lifting tasks or activities can put strain on the intervertebral discs. To lower the risk, take breaks, keep a good posture, and lift things correctly. 8. Keep hydrated: Drinking enough water to preserve the intervertebral discs’ water content helps sustain the discs’ shock-absorbing abilities. 9. Manage stress: Constant stress can cause tense muscles and hunched over posture. Use stress-reduction strategies, such as meditation, deep breathing, and relaxation techniques. 10. Use ergonomic equipment: Using furniture and equipment that supports good posture, whether at work or at home, can assist in lessening stress on the spine. 11. Physical examinations on a regular basis can help detect any early indications of disc degeneration or other problems. Early intervention can stop things from getting worse. 12. Stay active and adaptable: Stretching and yoga can help preserve spinal health and lower the chance of disc issues. These activities can also help you stay active and flexible. 13. Proper footwear: Wearing supportive footwear with adequate padding will assist in lessening the impact of walking or standing on the spine.
17.14 Conclusion Sum up, LDS, also referred to as LDH or herniated disc, is a common spinal condition marked by the protrusion of the intervertebral disc’s soft inner core through the tougher outer layer, which results in compression of the nearby nerves and produces pain, numbness, and weakness. LDS can significantly reduce a person’s quality of life by limiting their movement and day-to-day activities. A number of intricate elements interact to form LDS. The deterioration of the intervertebral discs and the risk of herniation can be attributed to age-related degeneration, genetic susceptibility, mechanical stress from repeated motions or bad posture, obesity, smoking, trauma, and even occupational vibration exposure. While each person’s specific etiology of LDS may differ, a combination of these variables plays a role. Strategies for the management and prevention of LDS are essential. The first line of treatment is conservative, which includes rest, physical therapy, pain management, and lifestyle changes. These techniques seek to reduce discomfort, bolster supporting muscles, and enhance posture. When symptoms develop or persist, surgical procedures like endoscopic discectomy or microdiscectomy may be thought about to relieve nerve compression. Being initiative-taking about spinal health is necessary to prevent LDS. Keeping a healthy weight, utilizing safe lifting techniques, exercising regularly, quitting smoking, employing ergonomics, and taking care of your posture can all help lower your risk of disc degeneration and herniation. In order to maintain spine health, regular physical examinations, and quick response to any indicators of
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discomfort are essential. Ultimately, having a thorough awareness of the risk factors, underlying causes, treatment options, and preventative actions for LDS equips people with the knowledge they need to make wise choices regarding their spinal health. People can take initiative-taking measures to lessen the effects of LDS and preserve a healthy spine throughout their lives by adopting a balanced lifestyle, obtaining medical advice when necessary, and giving priority to preventive activities.
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