Spectrums of Amyotrophic Lateral Sclerosis: Heterogeneity, Pathogenesis and Therapeutic Directions

SPECTRUMS OF AMYOTROPHIC LATERAL SCLEROSIS Discover state-of-the-art research findings on ALS from leading authors and editors in the field In Spectrums of Amyotrophic Lateral Sclerosis: Heterogeneity, Pathogenesis & Therapeutic Directions, distinguished researchers and editors Dr. Christopher A. Shaw and Jessica R. Morrice deliver a practical and powerful perspective on Amyotrophic Lateral Sclerosis (ALS) as a heterogeneous spectrum of disorders. This increasingly accepted point-of-view allows researchers and medical professionals to develop better targeted interventions and more precise therapies. In the book, readers will find chapters on a wide variety of critical issues facing ALS researchers and healthcare practitioners treating ALS sufferers, including animal models of ALS, neuronal support cells known to have a pivotal role in ALS, and current challenges in ALS clinical trials, among others. The authors describe pathologic features common to all cases of ALS and why animal models, though crucial, should be interpreted with caution. Finally, multiple genetic and environmental etiologies of the disease are discussed. Readers will also benefit from the inclusion of: A thorough introduction to ALS as a spectrum disease and the implications for models, therapeutic development and clinical trial design Explorations of the genetic basis of ALS, prospective sALS etiologies, and the involvement of microbiome in ALS Discussions of ALS-PDC and environmental risk factors, protein aggregation in ALS, defects in RNA metabolism in ALS, and the non-cell autonomous nature of ALS and the involvement of glial cells Examinations of animal models of ALS and perspectives on previously failed ALS therapeutics and current therapeutic strategies Perfect for clinical neurologists, healthcare providers and caretakers, clinicians, and researchers studying motor neuron disease, Spectrums of Amyotrophic Lateral Sclerosis: Heterogeneity, Pathogenesis & Therapeutic Directions is also an indispensable resource for the neurodegenerative research community, neurology residents, and graduate-level neuroscience students.

Table of Contents:
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