Huntington's disease : pathogenic mechanisms and implications for therapeutics /

Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders, characterized by a clinical trial of movement disorder, cognitive deficits, and psychiatric symptoms.

Bibliographic Details
Uniform Title:	Huntington's disease (Yang)
Corporate Author:	ScienceDirect (Online service)
Other Authors:	Yang, X. William (Editor), Thompson, Leslie M. (Professor) (Editor), Heiman, Myriam (Editor)
Format:	eBook
Language:	English
Published:	London : Academic Press, 2024.
Subjects:	Huntington's disease. Electronic books.
Online Access:	Connect to the full text of this electronic book

Table of Contents:

Intro
Title page
Table of Contents
Copyright
Dedication
Contributors
Preface
Chapter 1. Huntington's disease: Clinical features, genetic diagnosis, and brain imaging
Introduction
Clinical course
Juvenile Huntington's disease
Genetic diagnosis and genetic counseling
Imaging
Conclusion: Clinical aspects relevant for the development of disease-modifying therapies in Huntington's disease
List of abbreviations
Chapter 2. Revolutionizing clinical research and communication in Huntington's disease: The Huntington's disease integrated staging system (HD-ISS)
Introduction
Disease classification, measurement, and staging
The development of the HD-ISS
Applying the HD-ISS in research: New possibilities
Applying the HD-ISS in research: Practical questions
Applying the HD-ISS in research: Implications for people with Huntington's disease
Conclusion
Chapter 3. Huntington's disease genetics: Implications for pathogenesis
Description of inheritance
Chromosomal mapping of the HD genetic defect and its consequences
The HD genetic defect
The expanded HTT CAG repeat confers a gain of function
HD genotype-phenotype correlation
Modifiers of HD onset from human genetics
A model for HD pathogenesis from human genetics
Underpinnings of the modifier effects
Modifiers of other disease landmarks
HD diagnostics
What is the ultimate cause of neuronal loss?
Potential for developing an HD treatment from genetic knowledge
Conclusion
Chapter 4. The instability of the Huntington's disease CAG repeat mutation
Introduction: The critical role of CAG repeat length
Intergenerational repeat instability
Somatic repeat instability
Insights into CAG repeat instability from mouse models
Insights from human genetics
Conclusions and perspective.
Chapter 5. Mechanisms of somatic CAG-repeat expansions in Huntington's disease
Introduction
Current understanding of somatic repeat instability
Slip-out formation
Requirement of transcription and transcription-coupled repair for somatic repeat instability
Melting unusual structures at the repeat and modulating torsional tension
Many nucleases can act on slipped-DNA structures which may impact repeat instability
Gap-filling and ligation of the DNA backbone
What is still unclear?
Conclusion
Chapter 6. RNA-mediated pathogenic mechanisms in Huntington's disease
Expression of the huntingtin gene
Regulation of huntingtin transcription
Alternative processing of huntingtin pre-mRNA
Nuclear RNA "clusters" and RNA "foci" in HD mouse models and HD patient samples
Global aberrant RNA processing in HD
RNA-based mechanism of pathogenesis
Implications for therapy
Chapter 7. Huntingtin protein-protein interactions: From biology to therapeutic targets
Introduction
Two-hybrid HTT protein interaction mapping efforts
Cataloging of HTT interacting partners using (immuno)affinity-based purification approaches
Compilation and computational analysis of HTT PPIs from large- and small-scale PPI mapping studies
Outlook
Chapter 8. Repeat-associated non-AUG (RAN) translation and Huntington's disease: Pathology, mechanistic and therapeutic perspectives
Introduction to RAN translation
RAN proteins in Huntington's disease
RAN and polyGln proteins accumulate in distinct and vulnerable brain regions
Animal models of HD and RAN translation
RAN protein toxicity
Mechanistic focused therapeutics
Conclusions
Chapter 9. Proteostasis function and dysfunction in Huntington's disease
Introduction
Impact of mHTT protein on HD pathology and protein aggregation propensity.
Therapeutic opportunities
Conclusion and future directions
Chapter 13. Pathophysiology of synapses and circuits in Huntington disease
Clinical and genetic features of HD
Cortical-basal ganglia-thalamic-cortical loops regulate movement and are modulated by dopamine
Neuropathology
Measurable subclinical changes precede definitive motor diagnosis
Animal models of HD facilitate investigating brain changes before overt clinical diagnosis
Striatal microcircuit synapses
Synaptic alterations in basal ganglia nuclei downstream of striatal SPN
Neuronal excitability
Input-specific plasticity: Long-term potentiation and depression
Homeostatic plasticity
Altered corticostriatal and thalamostriatal connectivity in HD
Cortex motor and sensory function
Cortex reward pathways
Targeting synaptic and circuit changes to advance therapeutics in Huntington disease
Chapter 14. The role of glial pathology in Huntington's disease
The role of glial progenitor cells in HD pathogenesis
Astrocytic dysfunction in HD
The effects of HD pathology on oligodendrocytes and myelin
Synopsis
Chapter 15. Systems biology study of Huntington's disease
Introduction
Transcriptomic profiling of HD mice
Insights from transcriptomic studies of HD mouse models
Mechanisms implicated in striatal transcriptinopathy in HD
Epigenomic dysregulation in HD mice
Application of systems biology to study HD perturbations
Database of HD experimental data
Conclusions and perspectives
Chapter 16. Unbiased genome-wide approaches to identify vulnerability factors in Huntington's disease
Yeast model screening studies
Invertebrate model screening studies
Mammalian cell screening studies
Mammalian in vivo screening
Future directions.
Chapter 17. Striatal neuronal models of Huntington's disease via direct conversion: Modeling age-dependent disease phenotypes
MicroRNA-mediated conversion of human fibroblasts to neurons
Age maintenance in directly reprogrammed neurons
Recapitulation of adult-onset neuropathology of Huntington's disease using miRNAs-mediated reprogrammed neurons
Modeling disease-stage progression of Huntington's disease
Conclusion
Chapter 18. Genetic mouse models to explore Huntington's disease mechanisms and therapeutic strategies
Transgenic mHTT N-terminal fragment mouse models of HD
Full-length mHTT knock-in mouse models
Full-length human HTT transgenic models
Conclusions and perspectives
Chapter 19. Huntington's disease: From large animal models to HD gene therapy
Introduction to Huntington's disease neuropathology
Treatment of large animal models of HD
Conclusions
Chapter 20. Deep learning and deep phenotyping of HD iPSCs: Applications to study biology and test therapeutics
Background: Complexity in biology
A brief introduction to AI
Applications of DL to biology
Impact
Chapter 21. The promise of an underappreciated therapeutic target: Sleep and circadian rhythm dysfunction in Huntington's disease
Sleep disturbance in Huntington's disease: The evidence
Sleep disturbance in Huntington's disease: Preclinical models
Which comes first, HD or sleep dysfunction, and does it matter?
Circadian-based interventions in preclinical models
Pharmacological interventions
Conclusions
Chapter 22. Huntingtin lowering therapeutics
DNA oligonucleotides
Oligonucleotides that use RNA interference
siRNA oligonucleotides as therapeutic agents in HD
Gene editing to lower or correct mutant huntingtin mRNA or protein
AAV gene delivery for Huntington's disease: Background.