The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms

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