Journal Article10.1146/ANNUREV.NEURO.23.1.217
Glutamine Repeats and Neurodegeneration
Huda Y. Zoghbi,Harry T. Orr +1 more
1.3K
TL;DR: A model for pathogenesis that illuminates the unifying features of these polyglutamine disorders is concluded, and may prove relevant to other neurodegenerative disorders as well.
read more
Abstract: A growing number of neurodegenerative diseases have been found to result from the expansion of an unstable trinucleotide repeat. Over the past 6 years, researchers have focused on identifying the mechanism by which the expanded polyglutamine tract renders a protein toxic to a subset of vulnerable neurons. In this review, we summarize the clinicopathologic features of these disorders (spinobulbar muscular atrophy, Huntington disease, and the spinocerebellar ataxias, including dentatorubropallidoluysian atrophy), describe the genes involved and what is known about their products, and discuss the model systems that have lent insight into pathogenesis. The review concludes with a model for pathogenesis that illuminates the unifying features of these polyglutamine disorders. This model may prove relevant to other neurodegenerative disorders as well.
read more
Chat with Paper
AI Agents for this Paper
Find similar papers on Google Scholar, PubMed and Arxiv
Write a critical review of this paper
Analyze citations of this paper to find unaddressed research gaps
Citations
•Book
Impairment of the ubiquitin proteasome system by protein aggregation
Neil F. Bence,Roopal M. Sampat,Ron R. Kopito +2 more
- 01 Jan 2003
TL;DR: It is reported that protein aggregation directly impaired the function of the ubiquitin-proteasome system, suggesting a potential mechanism linking protein aggregation to cellular disregulation and cell death.
2.3K
Iron, brain ageing and neurodegenerative disorders
TL;DR: By studying the accumulation and cellular distribution of iron during ageing, this work should be able to increase the understanding of these neurodegenerative disorders and develop new therapeutic strategies.
Unfolding the role of protein misfolding in neurodegenerative diseases.
TL;DR: The aim of this article is to review the literature on the molecular mechanism of protein misfolding and aggregation, its role in Neurodegeneration and the potential targets for therapeutic intervention in neurodegenerative diseases.
1.5K
Folding proteins in fatal ways
TL;DR: Understanding some of the principles of protein folding has helped to explain how such diseases arise, with attendant therapeutic insights, and particularly challenging examples of such disorders occur in the post-mitotic environment of the neuron.
1.5K
Trinucleotide Repeat Disorders
Harry T. Orr,Huda Y. Zoghbi +1 more
TL;DR: It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.
1.4K
References
Inactivation of the mouse Huntington's disease gene homolog Hdh.
Mabel P. Duyao,Anna Auerbach,Angela Ryan,Francesca Persichetti,Glenn Barnes,Sandra M. McNeil,P. Ge,Jean-Paul Vonsattel,James F. Gusella,Alexandra L. Joyner,Marcy E. MacDonald +10 more
TL;DR: That Hdh inactivation does not mimic adult HD neuropathology suggests that the human disease involves a gain of function, and that huntingtin is critical early in embryonic development, before the emergence of the nervous system.
797
Absence epilepsy in tottering mutant mice is associated with calcium channel defects
Colin F. Fletcher,Cathleen M. Lutz,T. Norene O'Sullivan,John D. Shaughnessy,Richard Hawkes,Wayne N. Frankel,Neal G. Copeland,Nancy A. Jenkins +7 more
TL;DR: The first mutations in a mammalian central nervous system-specific voltage-sensitive calcium channel gene that is mutated in tg and tg(la) mice are defined and the first gene involved in absence epilepsy is identified.
795
Expanded Polyglutamine Protein Forms Nuclear Inclusions and Causes Neural Degeneration in Drosophila
John M. Warrick,Henry L. Paulson,Gladys L. Gray-Board,Quang T. Bui,Kenneth H. Fischbeck,Randall N. Pittman,Nancy M. Bonini +6 more
TL;DR: The results demonstrate that cellular mechanisms of human glutamine-repeat disease are conserved in invertebrates and will aid in identifying additional factors that modulate neurodegeneration.
696
Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract.
Y P Goldberg,Donald W. Nicholson,Dita M. Rasper,Michael Kalchman,H. B. Koide,Rona K. Graham,M. Bromm,Parsa Kazemi-Esfarjani,Nancy A. Thornberry,John P. Vaillancourt,Michael R. Hayden +10 more
TL;DR: The results show that huntingtin is cleaved by cysteine proteases and suggest that HD might be a disorder of inappropriate apoptosis, providing an explanation for the gain–of–function associated with GAG expansion.
667
Distinctive pharmacology and kinetics of cloned neuronal Ca2+ channels and their possible counterparts in mammalian CNS neurons.
Ji-Fang Zhang,Andrew D. Randall,Patrick T. Ellinor,William A. Horne,William A. Sather,T. Tanabe,Thomas Schwarz,Richard W. Tsien +7 more
TL;DR: This paper provides a brief overview of the diversity of voltage-gated Ca2+ channels and the recent work on neuronal Ca 2+ channels with novel pharmacological and biophysical properties that distinguish them from L, N, P or T-type channels.
658
Related Papers (5)
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