Journal ArticleDOI
Huntington's disease: from molecular pathogenesis to clinical treatment
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TLDR
Predictive genetic testing and findings of neuroimaging studies show that Huntington's disease is emerging as a model for strategies to develop therapeutic interventions, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset.Abstract:
Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, which encodes an abnormally long polyglutamine repeat in the huntingtin protein. Huntington's disease has served as a model for the study of other more common neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. These disorders all share features including: delayed onset; selective neuronal vulnerability, despite widespread expression of disease-related proteins during the whole lifetime; abnormal protein processing and aggregation; and cellular toxic effects involving both cell autonomous and cell-cell interaction mechanisms. Pathogenic pathways of Huntington's disease are beginning to be unravelled, offering targets for treatments. Additionally, predictive genetic testing and findings of neuroimaging studies show that, as in some other neurodegenerative disorders, neurodegeneration in affected individuals begins many years before onset of diagnosable signs and symptoms of Huntington's disease, and it is accompanied by subtle cognitive, motor, and psychiatric changes (so-called prodromal disease). Thus, Huntington's disease is also emerging as a model for strategies to develop therapeutic interventions, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset.read more
Citations
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Ferroptosis: Death by Lipid Peroxidation
TL;DR: The discovery of ferroptosis, the mechanism of ferraptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology are summarized.
Journal ArticleDOI
Huntington disease: natural history, biomarkers and prospects for therapeutics
Christopher A. Ross,Elizabeth Aylward,Edward J. Wild,Douglas R. Langbehn,Jeffrey D. Long,John H. Warner,Rachael I. Scahill,Blair R. Leavitt,Julie C. Stout,Jane S. Paulsen,R Reilmann,Paul G. Unschuld,Alice Wexler,Russell L. Margolis,Sarah J. Tabrizi +14 more
TL;DR: The natural history of HD is described, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features, and potential future roles of these biomarkers in clinical trials are reviewed.
Journal ArticleDOI
Multiple Wearable Sensors in Parkinson and Huntington Disease Individuals: A Pilot Study in Clinic and at Home
Jamie L. Adams,Karthik Dinesh,Mulin Xiong,Christopher G. Tarolli,Saloni Sharma,Nirav Sheth,Alexander J. Aranyosi,William Zhu,Steven Goldenthal,Kevin M. Biglan,E. Ray Dorsey,Gaurav Sharma +11 more
TL;DR: Among individuals with movement disorders, the use of wearable sensors in clinic and at home was feasible and well-received, and these sensors can identify statistically significant differences in activity profiles between individuals with movements disorders and those without.
Journal ArticleDOI
Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data
Sarah J. Tabrizi,Rachael I. Scahill,Gail Owen,Alexandra Durr,Blair R. Leavitt,Raymund A.C. Roos,Beth Borowsky,Bernhard Landwehrmeyer,Chris Frost,Hans J. Johnson,David Craufurd,David Craufurd,R Reilmann,Julie C. Stout,Douglas R. Langbehn +14 more
TL;DR: In early HD, imaging, quantitative motor, and cognitive measures were predictive of decline in total functional capacity and tracked longitudinal change, and neuropsychiatric changes consistent with frontostriatal pathological abnormalities were associated with this loss of functional capacity.
Journal ArticleDOI
The Biology of Huntingtin
TL;DR: This work reconsider the literature describing HTT-regulated molecular and cellular mechanisms that could be dysfunctional in HD and their possible physiological consequences for patients.
References
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Journal ArticleDOI
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
Marcy E. MacDonald,Christine Ambrose,Mabel P. Duyao,Richard H. Myers,Carol Lin,Lakshmi Srinidhi,Glenn Barnes,Sherryl A.M. Taylor,Marianne James,Nicolet Groot,Heather MacFarlane,Barbara Jenkins,Mary Anne Anderson,Nancy S. Wexler,James F. Gusella,Gillian P. Bates,Sarah Baxendale,Holger Hummerich,Susan F. Kirby,Mike North,S. Youngman,Richard Mott,Günther Zehetner,Zdenek Sedlacek,Annemarie Poustka,Anna-Maria Frischauf,Hans Lehrach,Alan Buckler,Deanna M. Church,Lynn Doucette-Stamm,Michael Conlon O'Donovan,Laura Riba-Ramirez,Manish A. Shah,Vincent P. Stanton,Scott A. Strobel,Karen M. Draths,Jennifer L. Wales,Peter B. Dervan,David E. Housman,Michael R. Altherr,Rita Shiang,Leslie M. Thompson,Thomas J. Fielder,John J. Wasmuth,Danilo A. Tagle,John Valdes,Lawrence W. Elmer,Marc W. Allard,Lucio H. Castilla,Manju Swaroop,Kris Blanchard,Francis S. Collins,Russell G. Snell,Tracey Holloway,Kathleen Gillespie,Nicole A. Datson,Duncan Shaw,Peter S. Harper +57 more
TL;DR: In this article, the authors used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect, which is expanded and unstable on HD chromosomes.
Journal Article
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group.
Manish A. Shah,Nicole A. Datson,Lakshmi Srinidhi,Vincent P. Stanton,Marcy E. MacDonald,Marc W. Allard,S. Youngman,Anna-Maria Frischauf,Richard Mott,KM Draths,Günther Zehetner,C. O’Donovan,Thomas J. Fielder,Bruce G. Jenkins,Manju Swaroop,Sherryl A.M. Taylor,Lynn Doucette-Stamm,Heather MacFarlane,Scott A. Strobel,H. E. McFarlane,Alan Buckler,Nicolet Groot,Holger Hummerich,Deanna M. Church,M. A. Anderson,Marianne James,Glenn Barnes,M. Christine,Francis S. Collins,Mabel P. Duyao,Peter B. Dervan,Gillian P. Bates,T Holloway,Peter S. Harper,TW Mcdonald,M North,K Blanchard,John J. Wasmuth,D. Shaw,Hans Lehrach,Danilo A. Tagle,Annemarie Poustka,David E. Housman,T. Huntington,Zdenek Sedlacek,Laura Riba,Susan F. Kirby,Carol Lin,Richard H. Myers,Leslie M. Thompson,Russell G. Snell,Michael Conlon O'Donovan,K Gillespie,Rita Shiang,Nancy S. Wexler,Christine Ambrose,J. F. Gusella,Sarah Baxendale,N. Groat,John Valdes +59 more
TL;DR: The Huntington's disease mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype.
Journal ArticleDOI
The functional anatomy of basal ganglia disorders.
TL;DR: A model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons is proposed, which suggests that the activity of sub Populations of Striatal projections neurons is differentially regulated by striatal afferents and that different striatal projections may mediate different aspects of motor control.
Journal ArticleDOI
Protein aggregation and neurodegenerative disease.
TL;DR: There is increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity, leading to approaches toward rational therapeutics.
Journal ArticleDOI
Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain
Marian DiFiglia,Ellen Sapp,Kathryn Chase,Stephen W. Davies,Gillian P. Bates,J. P. Vonsattel,Neil Aronin +6 more
TL;DR: An NH2-terminal fragment of mutant huntingtin was localized to neuronal intranuclear inclusions and dystrophic neurites in the HD cortex and striatum, and polyglutamine length influenced the extent of huntingtin accumulation in these structures.
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