• Contributors xiiiPreface xviiAcknowledgments xixForeword xxiCHAPTER 1 Clinical Heterogeneity of ALS – Implications for Models and Therapeutic Development 1Serena Lattante and Mario SabatelliIntroduction 1Clinical Heterogeneity of ALS 2Familial and Sporadic ALS 2Age of Onset 3Survival 3Classic ALS, LMN Form, and UMN Form 4Site of Onset 4Diagnosis of ALS 5ALS and Its Relationship with FrontotemporalDementia and Myopathies 5Pleiotropy of ALS Genes 6Genetic Models to Study ALS 8In Vivo Models 8In Vitro Models 9Conclusion 10Conflict of Interest 11Copyright and Permission Statement 11References 11CHAPTER 2 Genetic Basis of ALS 17Jay P. Ross, Patrick A. Dion, and Guy A. RouleauIntroduction 17Genes Causing ALS 18Superoxide Dismutase 1 (SOD1) 18TAR DNA‐Binding Protein 43 (TDP‐43) 19Fused in Sarcoma (FUS) 19Chromosome 9 Open Reading Frame 72 (C9orf72) 20Recently Discovered Genes 21Annexin A11 (ANXA11) 21Glycosyltransferase 8 Domain Containing 1 (GLT8D1) 23Stathmin‐2 (STMN2) 23Aspects of ALS Heritability 24Sporadic vs. Familial 24Penetrance and the Oligogenic Hypothesis 24Multistep Model 25Noncoding Variation 25Regulatory and Intronic Variants 25Epigenetics 26Conclusions 27Acknowledgments 27Conflict of Interest 27Copyright and Permission Statement 28References 28CHAPTER 3 Susceptibility Genes and Epigenetics in Sporadic ALS 35Jessica R. Morrice, Christopher A. Shaw,and Cheryl Y. Gregory‐EvansIntroduction 35Environmental Associations in sALS 36Genetic Basis of sALS 38Identification of sALS Susceptibility Genes 39Candidate sALS Susceptibility Genes 40Unc13a 40Dpp6 40C21orf2 41Epigenetic Mechanisms in sALS 41Methylation in sALS 41miRNAs in sALS 42Post‐Translational Histone Modification in sALS 43Epigenetic Analysis in Monozygotic sALS Twins 44Modifications to the Epigenome by Environmental Factors 44In Utero Environmental Exposures 45Environmental in Utero Epigenomic Alterations 45Post Utero Exposures 45Conclusion 46Conflict of Interest 46Copyright and Permission Statement 47References 47CHAPTER 4 The Lessons of ALS‐PDC – Environmental Factorsin ALS Etiology 57Christopher A. Shaw and Thomas E. MarlerIntroduction 57Koch’s Postulates in the Search of Etiological ALS Factors 58Neurological Disease Clusters 59The Natural History of ALS‐PDC 60Investigating Etiological Factors 62Identified Cycad Toxicants 67Aluminum and Ionic Etiologies for ALS‐PDC 69Other Molecules That Might Have Been Involved in ALS‐PDC 70A Putative Viral Etiology for ALS‐PDC on Guamand ALS in General 70The Continuing Importance of ALS‐PDC 71Summary and Conclusions 73Acknowledgments 74Conflict of Interest 74Copyright and Permission Statement 74References 75CHAPTER 5 The Microbiome of ALS – Does It Start from the Gut? 81Audrey Labarre and Alex ParkerIntroduction 81Recent Studies 82Animal and in vitro Studies 82Clinical Studies 91How Could the Microbiome Contribute to ALS? 92Gut Barrier and Membrane Permeability 93Inflammation and Immune Response 94Neurotoxins 95Energy Metabolism 96Microbiome Modulation as a Potential Therapeutic Avenue 96Conclusion 97Conflict of Interest 97Copyright and Permission Statement 97References 98Chapter 6 Protein Aggregation in Amyotrophic Lateral Sclerosis 105Christen G. Chisholm, Justin J. Yerbury,and Luke McAlaryIntroduction 105Pathological Protein Inclusions Associated with ALS 106Protein Homeostasis and Misfolded ProteinPartitioning in ALS 107Consequences of Protein Aggregation in ALS 108The Primary Aggregating Proteins in ALS 110Superoxide Dismutase‐1 (SOD1) 110Transactivated Response DNA BindingProtein 43 (TDP‐43) 111Fused in Sarcoma (FUS) 111Prion‐like Propagation of Protein Aggregation in ALS 112Conclusion 113Acknowledgments 114Conflict of Interest 114Copyright and Permission Statement 114References 114CHAPTER 7 Evidence for a Growing Involvement of Gliain Amyotrophic Lateral Sclerosis 123Rowan A. W. Radford, Andres Vidal‐Itriago,Natalie M. Scherer, Albert Lee, Manuel Graeber,Roger S. Chung, and Marco MorschIntroduction 123Non‐neuronal Cells Play Important Rolesin Neurodegeneration Including in ALS 123Glial Cells and Their Established Functions 123Neurodegeneration and the Role of Glial Cells 124Glia in ALS 124Glial Dysfunction Is a Common Hallmarkof ALS Patients 125Glial Activation in ALS Models 126Major Pathological Forms of ALS 126Microglia‐Related ALS Pathology 126Microglia in SOD1‐ALS Pathology 126Microglia in TDP‐43‐ALS Pathology 127Microglia in FUS‐ALS Pathology 128Astrocyte‐Related ALS Pathology 128Oligodendrocyte‐Related ALS Pathologyand Glial Inclusion Formation 129Glial Inclusion Formation in ALS 130Oligodendrocytes 130Astrocytes 131The Role of Glial Cells in SOD1 Pathology Might BeDifferent from Other Forms of ALS 131Conclusion 132Acknowledgments 134Conflict of Interest 134Copyright and Permission Statement 134References 134CHAPTER 8 Animal Models of ALS – Current and FuturePerspectives 143Robert A. Déziel, Amber L. Marriott, Denis G. Kay,and Daphne A. GillIntroduction 143The Clinical Manifestations of ALS 143Limb Onset 144Bulbar Onset 144Respiratory Onset 144Current and Experimental Pharmacological Interventions 145Riluzole 145Edaravone 146Future Directions for Pharmacological Interventions 146Causative Factors in the Development of ALS 146Genetic Factors 146Environmental and Epigenetic Factors 148Gut and Microbial Factors 148Animal Models of ALS 150One‐hit Models of ALS 150Multi‐hit Models of ALS 151Future Model Development 153Acknowledgments 153Conflict of Interest 154Copyright and Permission Statement 154References 154CHAPTER 9 Clinical Trials in ALS – Current Challengesand Strategies for Future Directions 161Kristiana Salmon and Angela Genge 161Introduction 161Challenges in ALS Clinical Trials 162Disease Heterogeneity 162Lack of Established Biomarkers 163Limitations of Conventional Outcome Measures 163ALSFRS‐R 163FVC/SVC 164HHD 164Survival vs. Function 164Phase II Trial “Paradox” 165Patient Recruitment and Retention 166Assumptions for Lead‐In Phases 166Navigating Regulatory Nuances 167Future Directions 167Advances in Disease Understanding and Assessment 168Disease Heterogeneity 168Emerging Biomarkers 168Novel Outcome Measures 169New Approaches to Trial Design 170Cautious Phase II Design 170Adaptive Trial Design 171Platform Trials 172Bayesian Statistics 172Education 173People Make or Break a Trial 173Conclusion 174Acknowledgments 175Conflict of Interest 175Copyright and Permission Statement 175References 175CHAPTER 10 Future Priorities and Directions in ALS Research and Treatment 181Jessica R. Morrice, Michael Kuo,and Christopher A. ShawIntroduction 181Etiological Heterogeneity of ALS 182ALS Risk Factors 183Cellular Dysfunction in ALS 185ALS as a “Treatable” Disease 186The Importance of Effective Biomarkers 187Future Therapeutic Avenues for a Heterogeneous Disease 188Ongoing Clinical Trials Using CuATSM 188Conclusions and the Road Forward in ALS Research and Treatment 190Conflict of Interest 191Copyright and Permission Statement 191References 191Index 000

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• Contributors xiiiPreface xviiAcknowledgments xixForeword xxiCHAPTER 1 Clinical Heterogeneity of ALS – Implications for Models and Therapeutic Development 1Serena Lattante and Mario SabatelliIntroduction 1Clinical Heterogeneity of ALS 2Familial and Sporadic ALS 2Age of Onset 3Survival 3Classic ALS, LMN Form, and UMN Form 4Site of Onset 4Diagnosis of ALS 5ALS and Its Relationship with FrontotemporalDementia and Myopathies 5Pleiotropy of ALS Genes 6Genetic Models to Study ALS 8In Vivo Models 8In Vitro Models 9Conclusion 10Conflict of Interest 11Copyright and Permission Statement 11References 11CHAPTER 2 Genetic Basis of ALS 17Jay P. Ross, Patrick A. Dion, and Guy A. RouleauIntroduction 17Genes Causing ALS 18Superoxide Dismutase 1 (SOD1) 18TAR DNA‐Binding Protein 43 (TDP‐43) 19Fused in Sarcoma (FUS) 19Chromosome 9 Open Reading Frame 72 (C9orf72) 20Recently Discovered Genes 21Annexin A11 (ANXA11) 21Glycosyltransferase 8 Domain Containing 1 (GLT8D1) 23Stathmin‐2 (STMN2) 23Aspects of ALS Heritability 24Sporadic vs. Familial 24Penetrance and the Oligogenic Hypothesis 24Multistep Model 25Noncoding Variation 25Regulatory and Intronic Variants 25Epigenetics 26Conclusions 27Acknowledgments 27Conflict of Interest 27Copyright and Permission Statement 28References 28CHAPTER 3 Susceptibility Genes and Epigenetics in Sporadic ALS 35Jessica R. Morrice, Christopher A. Shaw,and Cheryl Y. Gregory‐EvansIntroduction 35Environmental Associations in sALS 36Genetic Basis of sALS 38Identification of sALS Susceptibility Genes 39Candidate sALS Susceptibility Genes 40Unc13a 40Dpp6 40C21orf2 41Epigenetic Mechanisms in sALS 41Methylation in sALS 41miRNAs in sALS 42Post‐Translational Histone Modification in sALS 43Epigenetic Analysis in Monozygotic sALS Twins 44Modifications to the Epigenome by Environmental Factors 44In Utero Environmental Exposures 45Environmental in Utero Epigenomic Alterations 45Post Utero Exposures 45Conclusion 46Conflict of Interest 46Copyright and Permission Statement 47References 47CHAPTER 4 The Lessons of ALS‐PDC – Environmental Factorsin ALS Etiology 57Christopher A. Shaw and Thomas E. MarlerIntroduction 57Koch’s Postulates in the Search of Etiological ALS Factors 58Neurological Disease Clusters 59The Natural History of ALS‐PDC 60Investigating Etiological Factors 62Identified Cycad Toxicants 67Aluminum and Ionic Etiologies for ALS‐PDC 69Other Molecules That Might Have Been Involved in ALS‐PDC 70A Putative Viral Etiology for ALS‐PDC on Guamand ALS in General 70The Continuing Importance of ALS‐PDC 71Summary and Conclusions 73Acknowledgments 74Conflict of Interest 74Copyright and Permission Statement 74References 75CHAPTER 5 The Microbiome of ALS – Does It Start from the Gut? 81Audrey Labarre and Alex ParkerIntroduction 81Recent Studies 82Animal and in vitro Studies 82Clinical Studies 91How Could the Microbiome Contribute to ALS? 92Gut Barrier and Membrane Permeability 93Inflammation and Immune Response 94Neurotoxins 95Energy Metabolism 96Microbiome Modulation as a Potential Therapeutic Avenue 96Conclusion 97Conflict of Interest 97Copyright and Permission Statement 97References 98Chapter 6 Protein Aggregation in Amyotrophic Lateral Sclerosis 105Christen G. Chisholm, Justin J. Yerbury,and Luke McAlaryIntroduction 105Pathological Protein Inclusions Associated with ALS 106Protein Homeostasis and Misfolded ProteinPartitioning in ALS 107Consequences of Protein Aggregation in ALS 108The Primary Aggregating Proteins in ALS 110Superoxide Dismutase‐1 (SOD1) 110Transactivated Response DNA BindingProtein 43 (TDP‐43) 111Fused in Sarcoma (FUS) 111Prion‐like Propagation of Protein Aggregation in ALS 112Conclusion 113Acknowledgments 114Conflict of Interest 114Copyright and Permission Statement 114References 114CHAPTER 7 Evidence for a Growing Involvement of Gliain Amyotrophic Lateral Sclerosis 123Rowan A. W. Radford, Andres Vidal‐Itriago,Natalie M. Scherer, Albert Lee, Manuel Graeber,Roger S. Chung, and Marco MorschIntroduction 123Non‐neuronal Cells Play Important Rolesin Neurodegeneration Including in ALS 123Glial Cells and Their Established Functions 123Neurodegeneration and the Role of Glial Cells 124Glia in ALS 124Glial Dysfunction Is a Common Hallmarkof ALS Patients 125Glial Activation in ALS Models 126Major Pathological Forms of ALS 126Microglia‐Related ALS Pathology 126Microglia in SOD1‐ALS Pathology 126Microglia in TDP‐43‐ALS Pathology 127Microglia in FUS‐ALS Pathology 128Astrocyte‐Related ALS Pathology 128Oligodendrocyte‐Related ALS Pathologyand Glial Inclusion Formation 129Glial Inclusion Formation in ALS 130Oligodendrocytes 130Astrocytes 131The Role of Glial Cells in SOD1 Pathology Might BeDifferent from Other Forms of ALS 131Conclusion 132Acknowledgments 134Conflict of Interest 134Copyright and Permission Statement 134References 134CHAPTER 8 Animal Models of ALS – Current and FuturePerspectives 143Robert A. Déziel, Amber L. Marriott, Denis G. Kay,and Daphne A. GillIntroduction 143The Clinical Manifestations of ALS 143Limb Onset 144Bulbar Onset 144Respiratory Onset 144Current and Experimental Pharmacological Interventions 145Riluzole 145Edaravone 146Future Directions for Pharmacological Interventions 146Causative Factors in the Development of ALS 146Genetic Factors 146Environmental and Epigenetic Factors 148Gut and Microbial Factors 148Animal Models of ALS 150One‐hit Models of ALS 150Multi‐hit Models of ALS 151Future Model Development 153Acknowledgments 153Conflict of Interest 154Copyright and Permission Statement 154References 154CHAPTER 9 Clinical Trials in ALS – Current Challengesand Strategies for Future Directions 161Kristiana Salmon and Angela Genge 161Introduction 161Challenges in ALS Clinical Trials 162Disease Heterogeneity 162Lack of Established Biomarkers 163Limitations of Conventional Outcome Measures 163ALSFRS‐R 163FVC/SVC 164HHD 164Survival vs. Function 164Phase II Trial “Paradox” 165Patient Recruitment and Retention 166Assumptions for Lead‐In Phases 166Navigating Regulatory Nuances 167Future Directions 167Advances in Disease Understanding and Assessment 168Disease Heterogeneity 168Emerging Biomarkers 168Novel Outcome Measures 169New Approaches to Trial Design 170Cautious Phase II Design 170Adaptive Trial Design 171Platform Trials 172Bayesian Statistics 172Education 173People Make or Break a Trial 173Conclusion 174Acknowledgments 175Conflict of Interest 175Copyright and Permission Statement 175References 175CHAPTER 10 Future Priorities and Directions in ALS Research and Treatment 181Jessica R. Morrice, Michael Kuo,and Christopher A. ShawIntroduction 181Etiological Heterogeneity of ALS 182ALS Risk Factors 183Cellular Dysfunction in ALS 185ALS as a “Treatable” Disease 186The Importance of Effective Biomarkers 187Future Therapeutic Avenues for a Heterogeneous Disease 188Ongoing Clinical Trials Using CuATSM 188Conclusions and the Road Forward in ALS Research and Treatment 190Conflict of Interest 191Copyright and Permission Statement 191References 191Index 000

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• Contributors xiiiPreface xviiAcknowledgments xixForeword xxiCHAPTER 1 Clinical Heterogeneity of ALS – Implications for Models and Therapeutic Development 1Serena Lattante and Mario SabatelliIntroduction 1Clinical Heterogeneity of ALS 2Familial and Sporadic ALS 2Age of Onset 3Survival 3Classic ALS, LMN Form, and UMN Form 4Site of Onset 4Diagnosis of ALS 5ALS and Its Relationship with FrontotemporalDementia and Myopathies 5Pleiotropy of ALS Genes 6Genetic Models to Study ALS 8In Vivo Models 8In Vitro Models 9Conclusion 10Conflict of Interest 11Copyright and Permission Statement 11References 11CHAPTER 2 Genetic Basis of ALS 17Jay P. Ross, Patrick A. Dion, and Guy A. RouleauIntroduction 17Genes Causing ALS 18Superoxide Dismutase 1 (SOD1) 18TAR DNA‐Binding Protein 43 (TDP‐43) 19Fused in Sarcoma (FUS) 19Chromosome 9 Open Reading Frame 72 (C9orf72) 20Recently Discovered Genes 21Annexin A11 (ANXA11) 21Glycosyltransferase 8 Domain Containing 1 (GLT8D1) 23Stathmin‐2 (STMN2) 23Aspects of ALS Heritability 24Sporadic vs. Familial 24Penetrance and the Oligogenic Hypothesis 24Multistep Model 25Noncoding Variation 25Regulatory and Intronic Variants 25Epigenetics 26Conclusions 27Acknowledgments 27Conflict of Interest 27Copyright and Permission Statement 28References 28CHAPTER 3 Susceptibility Genes and Epigenetics in Sporadic ALS 35Jessica R. Morrice, Christopher A. Shaw,and Cheryl Y. Gregory‐EvansIntroduction 35Environmental Associations in sALS 36Genetic Basis of sALS 38Identification of sALS Susceptibility Genes 39Candidate sALS Susceptibility Genes 40Unc13a 40Dpp6 40C21orf2 41Epigenetic Mechanisms in sALS 41Methylation in sALS 41miRNAs in sALS 42Post‐Translational Histone Modification in sALS 43Epigenetic Analysis in Monozygotic sALS Twins 44Modifications to the Epigenome by Environmental Factors 44In Utero Environmental Exposures 45Environmental in Utero Epigenomic Alterations 45Post Utero Exposures 45Conclusion 46Conflict of Interest 46Copyright and Permission Statement 47References 47CHAPTER 4 The Lessons of ALS‐PDC – Environmental Factorsin ALS Etiology 57Christopher A. Shaw and Thomas E. MarlerIntroduction 57Koch’s Postulates in the Search of Etiological ALS Factors 58Neurological Disease Clusters 59The Natural History of ALS‐PDC 60Investigating Etiological Factors 62Identified Cycad Toxicants 67Aluminum and Ionic Etiologies for ALS‐PDC 69Other Molecules That Might Have Been Involved in ALS‐PDC 70A Putative Viral Etiology for ALS‐PDC on Guamand ALS in General 70The Continuing Importance of ALS‐PDC 71Summary and Conclusions 73Acknowledgments 74Conflict of Interest 74Copyright and Permission Statement 74References 75CHAPTER 5 The Microbiome of ALS – Does It Start from the Gut? 81Audrey Labarre and Alex ParkerIntroduction 81Recent Studies 82Animal and in vitro Studies 82Clinical Studies 91How Could the Microbiome Contribute to ALS? 92Gut Barrier and Membrane Permeability 93Inflammation and Immune Response 94Neurotoxins 95Energy Metabolism 96Microbiome Modulation as a Potential Therapeutic Avenue 96Conclusion 97Conflict of Interest 97Copyright and Permission Statement 97References 98Chapter 6 Protein Aggregation in Amyotrophic Lateral Sclerosis 105Christen G. Chisholm, Justin J. Yerbury,and Luke McAlaryIntroduction 105Pathological Protein Inclusions Associated with ALS 106Protein Homeostasis and Misfolded ProteinPartitioning in ALS 107Consequences of Protein Aggregation in ALS 108The Primary Aggregating Proteins in ALS 110Superoxide Dismutase‐1 (SOD1) 110Transactivated Response DNA BindingProtein 43 (TDP‐43) 111Fused in Sarcoma (FUS) 111Prion‐like Propagation of Protein Aggregation in ALS 112Conclusion 113Acknowledgments 114Conflict of Interest 114Copyright and Permission Statement 114References 114CHAPTER 7 Evidence for a Growing Involvement of Gliain Amyotrophic Lateral Sclerosis 123Rowan A. W. Radford, Andres Vidal‐Itriago,Natalie M. Scherer, Albert Lee, Manuel Graeber,Roger S. Chung, and Marco MorschIntroduction 123Non‐neuronal Cells Play Important Rolesin Neurodegeneration Including in ALS 123Glial Cells and Their Established Functions 123Neurodegeneration and the Role of Glial Cells 124Glia in ALS 124Glial Dysfunction Is a Common Hallmarkof ALS Patients 125Glial Activation in ALS Models 126Major Pathological Forms of ALS 126Microglia‐Related ALS Pathology 126Microglia in SOD1‐ALS Pathology 126Microglia in TDP‐43‐ALS Pathology 127Microglia in FUS‐ALS Pathology 128Astrocyte‐Related ALS Pathology 128Oligodendrocyte‐Related ALS Pathologyand Glial Inclusion Formation 129Glial Inclusion Formation in ALS 130Oligodendrocytes 130Astrocytes 131The Role of Glial Cells in SOD1 Pathology Might BeDifferent from Other Forms of ALS 131Conclusion 132Acknowledgments 134Conflict of Interest 134Copyright and Permission Statement 134References 134CHAPTER 8 Animal Models of ALS – Current and FuturePerspectives 143Robert A. Déziel, Amber L. Marriott, Denis G. Kay,and Daphne A. GillIntroduction 143The Clinical Manifestations of ALS 143Limb Onset 144Bulbar Onset 144Respiratory Onset 144Current and Experimental Pharmacological Interventions 145Riluzole 145Edaravone 146Future Directions for Pharmacological Interventions 146Causative Factors in the Development of ALS 146Genetic Factors 146Environmental and Epigenetic Factors 148Gut and Microbial Factors 148Animal Models of ALS 150One‐hit Models of ALS 150Multi‐hit Models of ALS 151Future Model Development 153Acknowledgments 153Conflict of Interest 154Copyright and Permission Statement 154References 154CHAPTER 9 Clinical Trials in ALS – Current Challengesand Strategies for Future Directions 161Kristiana Salmon and Angela Genge 161Introduction 161Challenges in ALS Clinical Trials 162Disease Heterogeneity 162Lack of Established Biomarkers 163Limitations of Conventional Outcome Measures 163ALSFRS‐R 163FVC/SVC 164HHD 164Survival vs. Function 164Phase II Trial “Paradox” 165Patient Recruitment and Retention 166Assumptions for Lead‐In Phases 166Navigating Regulatory Nuances 167Future Directions 167Advances in Disease Understanding and Assessment 168Disease Heterogeneity 168Emerging Biomarkers 168Novel Outcome Measures 169New Approaches to Trial Design 170Cautious Phase II Design 170Adaptive Trial Design 171Platform Trials 172Bayesian Statistics 172Education 173People Make or Break a Trial 173Conclusion 174Acknowledgments 175Conflict of Interest 175Copyright and Permission Statement 175References 175CHAPTER 10 Future Priorities and Directions in ALS Research and Treatment 181Jessica R. Morrice, Michael Kuo,and Christopher A. ShawIntroduction 181Etiological Heterogeneity of ALS 182ALS Risk Factors 183Cellular Dysfunction in ALS 185ALS as a “Treatable” Disease 186The Importance of Effective Biomarkers 187Future Therapeutic Avenues for a Heterogeneous Disease 188Ongoing Clinical Trials Using CuATSM 188Conclusions and the Road Forward in ALS Research and Treatment 190Conflict of Interest 191Copyright and Permission Statement 191References 191Index 000

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