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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Request a sales quoteHuntington'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.
- Reviews the clinical course and genetics of HD
- Reviews the biology of human huntingtin and HD-relevant cell types
- Reviews the wide range of pathobiology associated with mutant huntingtin
- Reviews genetic studies of HD and how these studies are informing the development of new therapeutic approaches
- Reviews new tools and model systems for basic and translational research in HD, including new human-derived model systems, as well as systems biology and artificial intelligence–driven approaches
- Provides an overview of new therapeutic approaches and current clinical programs in HD
Researchers and trainees in the field Huntington’s disease and related neurodegenerative disorders; Clinicians or clinical trainees in Neurology; Industry sectors/pharmaceutical or biotech companies: scientists and R&D or clinical leaders in these companies who are developing novel therapies for HD and related neurodegenerative disorders
- 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
- No. of pages: 618
- Language: English
- Edition: 1
- Published: February 7, 2024
- Imprint: Academic Press
- Paperback ISBN: 9780323956727
- eBook ISBN: 9780323956734
XY
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.
MH
Myriam Heiman
LT
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.