The Molecular and Cellular Basis of Neurodegenerative Diseases : Underlying Mechanisms

The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms presents the pathology, genetics, biochemistry and cell biology of the major human neurodegenerative diseases, including Alzheimer’s, Parkinson’s, frontotemporal dementia, ALS, Huntington’s, and prion diseases. Edited and authored by internationally recognized leaders in the field, the book's chapters explore their pathogenic commonalities and differences, also including discussions of animal models and prospects for therapeutics. Diseases are presented first, with common mechanisms later. Individual chapters discuss each major neurodegenerative disease, integrating this information to offer multiple molecular and cellular mechanisms that diseases may have in common. This book provides readers with a timely update on this rapidly advancing area of investigation, presenting an invaluable resource for researchers in the field. Key Features Covers the spectrum of neurodegenerative diseases and their complex genetic, pathological, biochemical and cellular features Focuses on leading hypotheses regarding the biochemical and cellular dysfunctions that cause neurodegeneration Details features, advantages and limitations of animal models, as well as prospects for therapeutic development Authored by internationally recognized leaders in the field Includes illustrations that help clarify and consolidate complex concepts Readership Graduate students in biological and biomedical sciences, neuroscientists, neurobiologists, neuropathologists, biological psychiatrists, post-doctoral fellows, researchers Front-matter_2018_The-Molecular-and-Cellular-Basis-of-Neurodegenerative-Dise The Molecular and Cellular Basis of Neurodegenerative Diseases Copyright_2018_The-Molecular-and-Cellular-Basis-of-Neurodegenerative-Disease Copyright Dedication_2018_The-Molecular-and-Cellular-Basis-of-Neurodegenerative-Diseas Dedication List-of-Contributo_2018_The-Molecular-and-Cellular-Basis-of-Neurodegenerativ List of Contributors Preface_2018_The-Molecular-and-Cellular-Basis-of-Neurodegenerative-Diseases Preface Chapter-1---Solving-the-Puzzle-o_2018_The-Molecular-and-Cellular-Basis-of-Ne 1 Solving the Puzzle of Neurodegeneration Introduction: The General Problem of Neurodegeneration Epidemiology and Clinical Presentation Molecular Pathology Genetics Molecular Clues to Mechanisms of Pathogenesis Common Themes and Controversies in Neurodegeneration Animal Models Prospects for Therapeutics Conclusions and Perspective References Chapter-2---Prion-Dis_2018_The-Molecular-and-Cellular-Basis-of-Neurodegenera 2 Prion Diseases Introduction and Historical Perspective Molecular Mechanism of Prion Propagation The Cellular Prion Protein: Structure and Proteolytic Processing Physiological Function of PrPC Mechanisms of PrPSc Toxicity: The N-Terminal Domain of PrPC Possess a Toxic Effector Activity Human Prion Diseases Animal Prion Diseases Prion Strains and Species Barriers Methods for Propagation and Detection of Prions Therapeutic Approaches PrPC and the Alzheimer’s Aβ Peptide Prion-like Propagation of Misfolded Proteins in Other Neurodegenerative Diseases Concluding Remarks References Chapter-3---Alzheimer-s-Disease--Toward-a-Quanti_2018_The-Molecular-and-Cell 3 Alzheimer’s Disease: Toward a Quantitative Biological Approach in Describing its Natural History and Underlying Mechanisms Quantitative Approach to Basic AD Demographics Change Over Time: (i) Biogenesis, Production, and Turnover of Aβ Change Over Time: (ii) The Accumulation, Spread, Propagation of Aβ Change Over Time: (iii) The Growth and Accumulation of Plaque Cores Change Over Time: (iv) Brain Atrophy Change Over Time: (v) Cognition Clearance Mechanisms and Impaired Phagocytosis Calculating Polygenic Risk Scores Disease-Modifying Strategies: Models of Aβ Accumulation in Alzheimer’s Disease—Implications for Aβ Amyloid-Targeting Therapies References Chapter-4---Neurodegeneration-and-t_2018_The-Molecular-and-Cellular-Basis-of 4 Neurodegeneration and the Ordered Assembly of Tau Introduction Tau Isoforms Tau Aggregation Genetics of MAPT Propagation of Tau Aggregates Strains of Aggregated Tau References Further Reading Chapter-5---Amyotrophic-Lateral-Scleros_2018_The-Molecular-and-Cellular-Basi 5 Amyotrophic Lateral Sclerosis and Other TDP-43 Proteinopathies TDP-43 Biology Amyotrophic Lateral Sclerosis ALS–TDP-43 ALS–SOD1 ALS-FUS ALS-C9ORF72 Mechanisms Dysregulated Nucleocytoplasmic Transport Proteostasis Clearance Mitochondrial Energy Production RNA Metabolism Axonal Dysfunction Excitotoxicity Oxidative Stress Neuroinflammation Other TDP-43 Proteinopathies Frontotemporal Dementia TDP-43 in Alzheimer’s Disease and Parkinsonian Syndromes Inclusion Body Myositis Conclusions References Chapter-6---Parkinson-s-Disease-and_2018_The-Molecular-and-Cellular-Basis-of 6 Parkinson’s Disease and Other Synucleinopathies Introduction: The Pathology of Parkinson’s Disease Protein Deposition Aggregation of α-Synuclein in PD The Broader Set of Synucleinopathies Changes in Cellularity Neuronal Loss Reactive Gliosis Genes Associated with Synucleinopathies SNCA Mutations and Familial PD Point Mutations Multiplications The SNCA Locus and Sporadic Synucleinopathies LRRK2 Other Genes Associated with Synucleinopathies Dominant Genes Recessive Genes Risk Factors Cellular Mechanisms in Synucleinopathies Neuronal Events Synuclein Accumulation Vesicular Trafficking Microtubule Function and Axonal Transport Lysosomal Dysfunction and the Autophagic Pathways Noncell-Autonomous Mechanisms Cell-to-Cell Spread Immunological Responses Trophic Support Summary References Chapter-7---Huntington-s-Disease-and-Other-Pol_2018_The-Molecular-and-Cellul 7 Huntington’s Disease and Other Polyglutamine Repeat Diseases: Molecular Mechanisms and Pathogenic Pathways Polyglutamine Expansion Aggregation Clearance of PolyQ Proteins Impairment of the Ubiquitin-Proteasome System The Role of Autophagy Transcriptional Dysregulation Mitochondrial Dysfunction Oxidative Stress/ATP Production Metabolism/Body Weight Mitochondria-Mediated Apoptotic Activation Mitochondrial Size, Shape, and Movement Posttranslational Modifications WARNING!!! DUMMY ENTRY Phosphorylation Sumoylation S-Nitrosylation Proteolytic Cleavage Caspases Calpains and Other Proteolytic Enzymes Nuclear Trafficking and Subcellular Localization Other Mechanisms Therapeutic Opportunities for polyQ Diseases WARNING!!! DUMMY ENTRY RNA Interference Antisense Oligonucleotides Zinc Finger Proteins CRISPR Concluding Remarks References Chapter-8---Prion-Like-Propagation-i_2018_The-Molecular-and-Cellular-Basis-o 8 Prion-Like Propagation in Neurodegenerative Diseases Introduction A Historical Perspective on Prion-Like Aspects in Neurodegenerative Diseases Koch’s Postulates and Infectivity Seeds of Infectivity Propagate Throughout History The Prion-Like Hypothesis Prion-Like Proteins in Neurodegenerative Diseases Amyloid-β Prions Tau Prions α-Synuclein Prions TDP-43 and FUS Prions SOD1 Prions Huntington Prions Mechanistic, Functional, and Pathogenic Properties of Prions Bacterial, Fungal, and Mammalian Prions Prions in Neurodegenerative Disorders Mechanisms of Transport and Cell-to-Cell Propagation Prion Propagation A Hitchhiker’s Guide to Infectivity Cellular Mechanisms in Prion-Like Diseases Mechanisms of Prion-Like Disease Propagation Studied In Vivo The Strain Hypothesis Strains in Transmissible Spongiform Encephalopathies Strains in Prion-Like Neurodegenerative Diseases Molecular Features of Strains How Prion Strains Might Come to Our Aid Therapeutic Strategies Diagnostic Strategies The Issue of Communicability of “Prion-Like” Diseases Conclusions References Chapter-9---Neurodegenerative-Disease_2018_The-Molecular-and-Cellular-Basis- 9 Neurodegenerative Diseases as Protein Folding Disorders Introduction Roles for Protein Folding, Modification, and Degradation What is Protein Misfolding and Why Does it Occur? Pathological Misfolding of Intrinsically Disordered and Mutant Proteins What Drives Misfolding and Amyloid Formation of Proteins? How do Misfolded Proteins and Aggregates Cause Neurodegeneration? Oligomer Hypothesis Neuroinflammation Proteostasis Disruption Synaptic Dysfunction How can Protein Misfolding be Targeted? Biomarkers for Early Detection Therapeutics Active Immunotherapy Passive Immunotherapy Gene Therapy Targeting Aggregation-Modulating Proteins Targeting Misfolded Proteins Directly Conclusions Dedication References Chapter-10---Heat-Shock-Proteins-and-Prot_2018_The-Molecular-and-Cellular-Ba 10 Heat Shock Proteins and Protein Quality Control in Alzheimer’s Disease General Introduction De Novo Folding, Refolding and Degradation: Triaging HSP and Proteasomal Degradation HSP and Autophagosomal Degradation Chaperone-Mediated Autophagy Macroautophagy HSP, UPS, and AD Phenotypical Changes in UPS in AD Phenotypical Changes in HSP in AD HSP: Preventing Neurodegenerative Effects of Aβ and Tau HSPs and Aß Peptides HSP Effects on Aß Peptide Aggregation In Vitro: Work With Purified Proteins HSP Effects on Aß Peptide Aggregation In Vitro: Work With Cell Models HSP Effects on Aß Peptide Aggregation In Vivo: Work With Organismal Models HSPs and Tau HSP Effects on Tau Aggregation In Vitro: Work With Purified Proteins HSP Effects on Tau Aggregation In Vitro: Work With Cell Models HSP Effects on Tau Aggregation In Vivo: Work With Organismal Models Cell Nonautonomous Effects of HSPs Hsp’s in Astrocytes/Glial Extracellular HSP—Paracrine Effects Cell Nonautonomous Regulation of Chaperones—Endocrine Effects HSPs, PQC and Extracellular Release of Aβ or Tau Perspectives References Chapter-11---Neurodegenerative-Di_2018_The-Molecular-and-Cellular-Basis-of-N 11 Neurodegenerative Diseases and Autophagy Autophagy Cell Biology Key Autophagy Machinery ATGs are Organized in Signaling Modules Upstream of LC3 Conjugation Autophagosome Membrane Trafficking Events Key Signaling Pathways Selective Autophagy Lysosomes Autophagy in Neuronal Physiology Autophagy in Neurodegenerative Diseases Alzheimer’s Disease Tauopathies Parkinson’s Disease Polyglutamine Disorders Amyotrophic Lateral Sclerosis Hereditary Spastic Paraplegias Lafora Disease Dynein and Dynamin Mutations Diseases Resulting from Mutations in Core Autophagy Genes Lysosomal Disorders Autophagy Upregulation Trehalose Rapamycin Repurposing of FDA-Approved Drugs as Autophagy Upregulators References Further Reading Chapter-12---Neurodegenerative-Dise_2018_The-Molecular-and-Cellular-Basis-of 12 Neurodegenerative Diseases and Axonal Transport Introduction to Axonal Transport Axonal Transport and Neurodegenerative Disease Alzheimer’s Disease Huntington’s and Other Polyglutamine Diseases Spinal and Bulbar Muscular Atrophy Hereditary Spastic Paraplegia Amyotrophic Lateral Sclerosis Charcot–Marie–Tooth Disease Parkinson’s Disease and Related Synucleinopathies Frontotemporal Dementia (FTD) and Related Tauopathies Conclusion References Chapter-13---Mitochondrial-Function-a_2018_The-Molecular-and-Cellular-Basis- 13 Mitochondrial Function and Neurodegenerative Diseases Introduction Mitochondria and Bioenergetics Section Overview Mitochondrial Structure Mitochondrial DNA The Respiratory Chain Mitochondrial Biogenesis Fusion/Fission Autophagy and Mitophagy The Mitochondrial Unfolded Protein Response Apoptosis and Cell Death Free Radical and Redox Biology Mitochondria in Neurodegenerative Diseases Section Overview Diseases Arising Exclusively from mtDNA Mutations Diseases Arising Exclusively from Nuclear DNA Mutations Alzheimer’s Disease Parkinson’s Disease Amyotrophic Lateral Sclerosis Therapeutic Targeting of Mitochondria Conclusions References Chapter-14---Non-cell-Autonomous-Degenerati_2018_The-Molecular-and-Cellular- 14 Non-cell Autonomous Degeneration: Role of Astrocytes in Neurodegenerative Diseases Introduction Astrocytes in Amyotrophic Lateral Sclerosis Astrocytes in Alzheimer’s Disease Astrocytes in Parkinson’s Disease Astrocytes in Huntington’s Disease Astrocytes in Spinocerebellar Ataxia Type 7 Non-cell Autonomous Roles of Astrocytes in Other Diseases Perspectives References Chapter-15---Neurodegenerative-Disea_2018_The-Molecular-and-Cellular-Basis-o 15 Neurodegenerative Diseases and RNA-Mediated Toxicity The Identification of RNA-Mediated Toxicity: The Myotonic Dystrophies and CTG Repeats The Sequestration Hypothesis Additional CTG Repeat-Related Diseases: Variations on a Theme Spinocerebellar Ataxia (SCA) Type 8 Huntington’s Disease-Like 2 Fuchs Endothelial Corneal Dystrophy RNA Foci and the Sequestration Hypothesis in Other Repeat-Associated Diseases Fragile X-Associated Tremor/Ataxia Syndrome Models of FXTAS Support an RNA-Mediated Mechanism Identifying the RBPs Sequestered by CGG Repeats Protein-Coding CAG Repeats in Huntington’s Disease (HD) and Other Polyglutamine Disorders Pentanucleotide and Hexanucleotide Repeats in Inherited SCAs Spinocerebellar Ataxia Type 10 Spinocerebellar Ataxia Type 31 Spinocerebellar Ataxia Type 36 Hexanucleotide GGGGCC repeats in C9orf72-Associated ALS and FTD (c9FTD/ALS) Bidirectional Transcription Repeat-Associated Non-ATG (RAN) Translation: When RNA Toxicity Results in Proteotoxicity RAN-Translated Proteins as Mediators of Disease The c9-RAN Proteins FMRpolyG and FMRpolyA in FXTAS RAN Translation in Huntington’s Disease The Mechanism of RAN Translation Conclusions and Therapeutic Directions References Chapter-16---Neuroinflammation-in-Age-_2018_The-Molecular-and-Cellular-Basis 16 Neuroinflammation in Age-Related Neurodegenerative Diseases Peripheral and Brain-Immune Mediators in Brain Health and Disease Contributors to the CNS Inflammatory Environment Microglia Macrophages T cells Astrocytes Regulation of Neuroinflammation Lymphatics and DCLNs Blood–Brain Barrier Cytokine signaling—TNF as a model The Role of Inflammation in Age-Related Neurodegenerative Disease: A Paradigm Shift The Role of Peripheral Inflammation in Neurodegenerative Disease Inflammatory Risk Factors for AD Alterations in Trafficking of Peripheral Immune Cells to Brain Chronic Peripheral Inflammation as a Risk Factor for Neurodegenerative Disease The Permissive Environment for Neurodegeneration How Does the Prion-Like Cascade of Protein Aggregation Begin? Is There a Path Forward for Therapeutic Intervention? Modulation of Peripheral Immune Cell Activation and/or Their Trafficking May Be a Potential Therapeutic Strategy Second-Hit Model of Progression of AD-like Pathology Assessing Changes in Peripheral Immune Cell Populations in At-Risk Human Populations References Chapter-17---Neurodegenerative-Dise_2018_The-Molecular-and-Cellular-Basis-of 17 Neurodegenerative Diseases and the Aging Brain General Mechanisms Underlying Neuronal Cell Dysfunction and Cognitive Decline Protein Degradation and Synapse Loss Unfolded Protein Response Ubiquitin–Proteasome Autophagy Oxidative Damage in the Aging and Neurodegenerating Brain DNA Break Repair in the Neurodegenerating Brain DNA Damage Reinforces the Metabolic and Gene Expression Changes in the Aging and Neurodegenerating Brain Conclusions References Index_2018_The-Molecular-and-Cellular-Basis-of-Neurodegenerative-Diseases Index

The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms presents the pathology, genetics, biochemistry and cell biology of the major human neurodegenerative diseases, including Alzheimer’s, Parkinson’s, frontotemporal dementia, ALS, Huntington’s, and prion diseases. Edited and authored by internationally recognized leaders in the field, the book's chapters explore their pathogenic commonalities and differences, also including discussions of animal models and prospects for therapeutics. Diseases are presented first, with common mechanisms later. Individual chapters discuss each major neurodegenerative disease, integrating this information to offer multiple molecular and cellular mechanisms that diseases may have in common.

This book provides readers with a timely update on this rapidly advancing area of investigation, presenting an invaluable resource for researchers in the field.

• Covers the spectrum of neurodegenerative diseases and their complex genetic, pathological, biochemical and cellular features
• Focuses on leading hypotheses regarding the biochemical and cellular dysfunctions that cause neurodegeneration
• Details features, advantages and limitations of animal models, as well as prospects for therapeutic development
• Authored by internationally recognized leaders in the field
• Includes illustrations that help clarify and consolidate complex concepts