Huntington’s Disease

Pathogenic Mechanisms and Implications for Therapeutics

1st Edition - February 7, 2024
Editors: X. William Yang, Myriam Heiman, Leslie M. Thompson
Language: English
Paperback ISBN:
9 7 8 - 0 - 3 2 3 - 9 5 6 7 2 - 7
eBook ISBN:
9 7 8 - 0 - 3 2 3 - 9 5 6 7 3 - 4

Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders, characterized by a clinical triad of movement disorder, cognitive deficits, an… Read more

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Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders, characterized by a clinical triad of movement disorder, cognitive deficits, and psychiatric symptoms. Huntington’s Disease: Pathogenic Mechanisms and Implications for Therapeutics reviews the most up-do-date content on HD pathogenic mechanisms and cutting-edge thinking on therapeutic strategies for HD. Chapters explore areas that include the clinical features and genetic studies of HD, the cellular and molecular biology of normal huntingtin, a range of HD models, the diverse pathogenic mechanisms linked to mutant huntingtin, new approaches to HD pathogenesis, as well as emerging preclinical therapeutic approaches and clinical programs in the field.

Cover image
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
mHTT interactions with the translation machinery
mHTT interactions with molecular chaperones
Pathways implicated in mHTT clearance
mHTT sequestration—beneficial or deleterious?
A vicious cycle links proteostasis dysfunction and HD pathology
Perspectives
Chapter 10. Autophagy and Huntington's disease
Introduction
Autophagy, three pathways trafficking cytosolic cargo to the lysosome
Autophagy: A therapeutic avenue for HD?
Selective autophagy: No longer simply “bulk degradation”
Dysfunctional autophagy in Huntington's disease
Conclusion
Chapter 11. SUMO modification in Huntington's disease: Unraveling complex mechanisms for therapeutic insights
Introduction
Unveiling the intricate machinery behind SUMOylation
SUMO's journey in HD: Tracing SUMO's path in Huntington's disease research
Guiding the way: E3 SUMO ligases and their role in regulating HTT protein dynamics
Balancing act: How SUMO tips the scale of protein homeostasis
SUMO at the crossroads of cellular stress: Navigating the relationship with stress granules
Disruption of the nuclear pore and altered nucleocytoplasmic transport in HD: A role for SUMO?
Synaptic SUMO: Bridging the gap between molecular modification and neuronal communication
Small modifier, big role: How SUMO orchestrates DNA damage repair
Summary and future directions: Implications for therapy
Chapter 12. Selective vulnerability in Huntington's disease: From excitotoxicity, mitochondrial dysfunction, and transcription dysregulation to therapeutic opportunity
Selective vulnerability in Huntington's disease
Possible mechanisms underlying corticostriatal degeneration in HD
Discovery of mitochondrial dysfunction in HD
PGC-1α
p53 and mitochondrial dysfunction in HD
Heat Shock Transcription Factor 1
Peroxisome proliferator–activated receptors
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
Micro-RNA: Its utility for viral-based delivery to brain in HD
Challenges for AAV gene therapy in HD
Stabilization of pseudo-exons in the human huntingtin gene, leading to nonsense-mediated decay of huntingtin mRNA
CAG expansion as a target for therapy: Zinc-finger proteins
Small molecule interaction with the CAG repeat: Naphthyridine-Azaquinolone
Preventing somatic lengthening of CAG repeat length, a tractable therapeutic strategy
Recent clinical trials testing lowering of mutant HTT
Commentary and outlook
Chapter 23. Gene editing for HD: Therapeutic prospects
Introduction
Overview of mHTT-selective gene editing strategies
SNP-based strategies
(CAG)n-based strategies
HTT mutation correction strategies
Targeting HD modifier genes
Perspective
Chapter 24. Current clinical trials of new therapeutic agents for Huntington's disease
Introduction
Phase I clinical trials
Phase II clinical trials
Phase III clinical trials
Regulatory approval of clinical trials
Conclusions and future studies
Potential novel therapeutic approaches for HD
Challenges and opportunities in clinical trial design and conduct in HD
Index

X. William Yang

Dr. X. William Yang completed his B.S./M.S. degrees in Molecular Biophysics & Biochemistry at Yale University in 1991. He obtained M.D./Ph.D. training at Rockefeller University (Ph.D., 1998) and Weill Medical College of Cornell University (M.D., 2000). He co-invented the technology to engineer Bacterial Artiﬁcial Chromosomes (BACs) and to generate BAC transgenic mice. His laboratory at UCLA (established in 2002) pioneered the use of a BAC transgenic approach in mice to study pathogenesis of neurodegenerative disorders including Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. The Yang lab has also applied novel genetic and systems biology approaches to study molecular networks in healthy and disease brains, and to study brain-wide morphology of genetically-defined neurons. He is a recipient of BRAIN Initiative Awards from NIH, Brain Disorder Award from McKnight Foundation, the Leslie Gehry Brenner Prize for Innovation in Science in 2014, and is an elected member of the American Society for Clinical Investigation.

Affiliations and expertise

University of California, Los Angeles

Myriam Heiman

Myriam Heiman and her lab use HD patient tissue, as well as mouse and cell models of HD to understand why some cells are more or less vulnerable to the mutant HD gene, and use knowledge of these intrinsic differences to identify new therapeutic targets for HD. Dr. Heiman has pioneered the use of in vivo genetic screening in the mammalian brain, as well as the use of novel single-cell and cell type-specific transcriptional profiling tools to study HD. Her work has recently pointed to the importance of neuronal innate immune activation and cell type-specific mitochondrial dysfunction in HD pathogenesis. Myriam is the recipient of several awards, including an Early Career Investigators Innovation Award from the Bumpus Foundation and a EUREKA grant from the National Institutes of Health.

Affiliations and expertise

Picower Institute for Learning and Memory

Leslie M. Thompson

Dr. Thompson is a Donald Bren and Chancellor’s Professor in the Departments of Psychiatry and Human Behavior and Neurobiology and Behavior at the University of California Irvine. She has studied Huntington’s disease (HD) for most of her scientific career and was a member of the international consortium that identified the causative gene for HD in 1993. Since that time, the Thompson laboratory has been actively engaged in investigating the fundamental molecular and cellular events that underlie how the mutant HD gene causes degeneration of specific brain cell populations to induce motor and cognitive decline and premature death of patients with the ultimate goal to develop new treatments, including stem-cell based treatments. Dr. Thompson is the recipient of several awards including the HDF Lesley Gehry Brenner Award for Scientific Innovation in 2013, an NIH Research Program R35 Award and was elected an AAAS fellow in 2013.

Affiliations and expertise

University of California, Irvine

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Social Sciences & Humanities

Health

Huntington’s Disease

Pathogenic Mechanisms and Implications for Therapeutics

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X. William Yang

Myriam Heiman

Leslie M. Thompson