Spectrums of Amyotrophic Lateral Sclerosis

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.

Résumé
SPECTRUMS OF AMYOTROPHIC LATERAL SCLEROSIS Discover state-of-the-art research findings on ALS from leading authors and editors in the fieldIn 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 strategiesPerfect 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.

Contenu
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 DNABinding Protein 43 (TDP43) 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

Stathmin2 (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. GregoryEvans

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

PostTranslational 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 ALSPDC 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 ALSPDC 60

Investigating Etiological Factors 62

Identified Cycad Toxicants 67

Aluminum and Ionic Etiologies for ALSPDC 69

Other Molecules That Might Have Been Involved in ALSPDC 70

A Putative Viral Etiology for ALSPDC on Guam

and ALS in General 70

The Continuing Importance of ALSPDC 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 Ener...