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Spectrums of Amyotrophic Lateral Sclerosis

Heterogeneity, Pathogenesis and Therapeutic Directions

Shaw, Christopher A. / Morrice, Jessia R. (Herausgeber)

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1. Auflage Mai 2021
240 Seiten, Hardcover
Wiley & Sons Ltd

ISBN: 978-1-119-74549-5
John Wiley & Sons

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Contributors xiii

Preface xvii

Acknowledgments xix

Foreword xxi

CHAPTER 1 Clinical Heterogeneity of ALS - Implications for Models and Therapeutic Development 1

Serena Lattante and Mario Sabatelli

Introduction 1

Clinical Heterogeneity of ALS 2

Familial and Sporadic ALS 2

Age of Onset 3

Survival 3

Classic ALS, LMN Form, and UMN Form 4

Site of Onset 4

Diagnosis of ALS 5

ALS and Its Relationship with Frontotemporal

Dementia and Myopathies 5

Pleiotropy of ALS Genes 6

Genetic Models to Study ALS 8

In Vivo Models 8

In Vitro Models 9

Conclusion 10

Conflict of Interest 11

Copyright and Permission Statement 11

References 11

CHAPTER 2 Genetic Basis of ALS 17

Jay P. Ross, Patrick A. Dion, and Guy A. Rouleau

Introduction 17

Genes Causing ALS 18

Superoxide Dismutase 1 (SOD1) 18

TAR DNA-Binding Protein 43 (TDP-43) 19

Fused in Sarcoma (FUS) 19

Chromosome 9 Open Reading Frame 72 (C9orf72) 20

Recently Discovered Genes 21

Annexin A11 (ANXA11) 21

Glycosyltransferase 8 Domain Containing 1 (GLT8D1) 23

Stathmin-2 (STMN2) 23

Aspects of ALS Heritability 24

Sporadic vs. Familial 24

Penetrance and the Oligogenic Hypothesis 24

Multistep Model 25

Noncoding Variation 25

Regulatory and Intronic Variants 25

Epigenetics 26

Conclusions 27

Acknowledgments 27

Conflict of Interest 27

Copyright and Permission Statement 28

References 28

CHAPTER 3 Susceptibility Genes and Epigenetics in Sporadic ALS 35

Jessica R. Morrice, Christopher A. Shaw,

and Cheryl Y. Gregory-Evans

Introduction 35

Environmental Associations in sALS 36

Genetic Basis of sALS 38

Identification of sALS Susceptibility Genes 39

Candidate sALS Susceptibility Genes 40

Unc13a 40

Dpp6 40

C21orf2 41

Epigenetic Mechanisms in sALS 41

Methylation in sALS 41

miRNAs in sALS 42

Post-Translational Histone Modification in sALS 43

Epigenetic Analysis in Monozygotic sALS Twins 44

Modifications to the Epigenome by Environmental Factors 44

In Utero Environmental Exposures 45

Environmental in Utero Epigenomic Alterations 45

Post Utero Exposures 45

Conclusion 46

Conflict of Interest 46

Copyright and Permission Statement 47

References 47

CHAPTER 4 The Lessons of ALS-PDC - Environmental Factors

in ALS Etiology 57

Christopher A. Shaw and Thomas E. Marler

Introduction 57

Koch's Postulates in the Search of Etiological ALS Factors 58

Neurological Disease Clusters 59

The Natural History of ALS-PDC 60

Investigating Etiological Factors 62

Identified Cycad Toxicants 67

Aluminum and Ionic Etiologies for ALS-PDC 69

Other Molecules That Might Have Been Involved in ALS-PDC 70

A Putative Viral Etiology for ALS-PDC on Guam

and ALS in General 70

The Continuing Importance of ALS-PDC 71

Summary and Conclusions 73

Acknowledgments 74

Conflict of Interest 74

Copyright and Permission Statement 74

References 75

CHAPTER 5 The Microbiome of ALS - Does It Start from the Gut? 81

Audrey Labarre and Alex Parker

Introduction 81

Recent Studies 82

Animal and in vitro Studies 82

Clinical Studies 91

How Could the Microbiome Contribute to ALS? 92

Gut Barrier and Membrane Permeability 93

Inflammation and Immune Response 94

Neurotoxins 95

Energy Metabolism 96

Microbiome Modulation as a Potential Therapeutic Avenue 96

Conclusion 97

Conflict of Interest 97

Copyright and Permission Statement 97

References 98

Chapter 6 Protein Aggregation in Amyotrophic Lateral Sclerosis 105

Christen G. Chisholm, Justin J. Yerbury,

and Luke McAlary

Introduction 105

Pathological Protein Inclusions Associated with ALS 106

Protein Homeostasis and Misfolded Protein

Partitioning in ALS 107

Consequences of Protein Aggregation in ALS 108

The Primary Aggregating Proteins in ALS 110

Superoxide Dismutase-1 (SOD1) 110

Transactivated Response DNA Binding

Protein 43 (TDP-43) 111

Fused in Sarcoma (FUS) 111

Prion-like Propagation of Protein Aggregation in ALS 112

Conclusion 113

Acknowledgments 114

Conflict of Interest 114

Copyright and Permission Statement 114

References 114

CHAPTER 7 Evidence for a Growing Involvement of Glia

in Amyotrophic Lateral Sclerosis 123

Rowan A. W. Radford, Andres Vidal-Itriago,

Natalie M. Scherer, Albert Lee, Manuel Graeber,

Roger S. Chung, and Marco Morsch

Introduction 123

Non-neuronal Cells Play Important Roles

in Neurodegeneration Including in ALS 123

Glial Cells and Their Established Functions 123

Neurodegeneration and the Role of Glial Cells 124

Glia in ALS 124

Glial Dysfunction Is a Common Hallmark

of ALS Patients 125

Glial Activation in ALS Models 126

Major Pathological Forms of ALS 126

Microglia-Related ALS Pathology 126

Microglia in SOD1-ALS Pathology 126

Microglia in TDP-43-ALS Pathology 127

Microglia in FUS-ALS Pathology 128

Astrocyte-Related ALS Pathology 128

Oligodendrocyte-Related ALS Pathology

and Glial Inclusion Formation 129

Glial Inclusion Formation in ALS 130

Oligodendrocytes 130

Astrocytes 131

The Role of Glial Cells in SOD1 Pathology Might Be

Different from Other Forms of ALS 131

Conclusion 132

Acknowledgments 134

Conflict of Interest 134

Copyright and Permission Statement 134

References 134

CHAPTER 8 Animal Models of ALS - Current and Future

Perspectives 143

Robert A. Déziel, Amber L. Marriott, Denis G. Kay,

and Daphne A. Gill

Introduction 143

The Clinical Manifestations of ALS 143

Limb Onset 144

Bulbar Onset 144

Respiratory Onset 144

Current and Experimental Pharmacological Interventions 145

Riluzole 145

Edaravone 146

Future Directions for Pharmacological Interventions 146

Causative Factors in the Development of ALS 146

Genetic Factors 146

Environmental and Epigenetic Factors 148

Gut and Microbial Factors 148

Animal Models of ALS 150

One-hit Models of ALS 150

Multi-hit Models of ALS 151

Future Model Development 153

Acknowledgments 153

Conflict of Interest 154

Copyright and Permission Statement 154

References 154

CHAPTER 9 Clinical Trials in ALS - Current Challenges

and Strategies for Future Directions 161

Kristiana Salmon and Angela Genge 161

Introduction 161

Challenges in ALS Clinical Trials 162

Disease Heterogeneity 162

Lack of Established Biomarkers 163

Limitations of Conventional Outcome Measures 163

ALSFRS-R 163

FVC/SVC 164

HHD 164

Survival vs. Function 164

Phase II Trial "Paradox" 165

Patient Recruitment and Retention 166

Assumptions for Lead-In Phases 166

Navigating Regulatory Nuances 167

Future Directions 167

Advances in Disease Understanding and Assessment 168

Disease Heterogeneity 168

Emerging Biomarkers 168

Novel Outcome Measures 169

New Approaches to Trial Design 170

Cautious Phase II Design 170

Adaptive Trial Design 171

Platform Trials 172

Bayesian Statistics 172

Education 173

People Make or Break a Trial 173

Conclusion 174

Acknowledgments 175

Conflict of Interest 175

Copyright and Permission Statement 175

References 175

CHAPTER 10 Future Priorities and Directions in ALS Research and Treatment 181

Jessica R. Morrice, Michael Kuo,

and Christopher A. Shaw

Introduction 181

Etiological Heterogeneity of ALS 182

ALS Risk Factors 183

Cellular Dysfunction in ALS 185

ALS as a "Treatable" Disease 186

The Importance of Effective Biomarkers 187

Future Therapeutic Avenues for a Heterogeneous Disease 188

Ongoing Clinical Trials Using CuATSM 188

Conclusions and the Road Forward in ALS Research and Treatment 190

Conflict of Interest 191

Copyright and Permission Statement 191

References 191

Index 000