Journal ArticleDOI
Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain
Henry L. Paulson,Sonal S. Das,Peter B. Crino,Matthew K. Perez,Sonal C. Patel,Denise Gotsdiner,Kenneth H. Fischbeck,Randall N. Pittman +7 more
TLDR
It is concluded that in MJD, as in other polyglutamine repeat diseases, cellular expression of the disease gene is not itself sufficient to cause neuronal degeneration; other cell‐specific factors must be invoked to explain the restricted neuropathology seen inMJD.Abstract:
Machado-Joseph disease (MJD) is one of at least six neurodegenerative diseases caused by expansion of a CAG repeat encoding a polyglutamine tract in the disease protein. To study the molecular mechanism of disease, we isolated both normal and expanded repeat MJD1 cDNAs, and generated antiserum against the recombinant gene product, called ataxin-3. Using this antiserum, we demonstrate that in disease tissue, both the normal and mutant ataxin-3 protein are expressed throughout the body and in all regions of the brain examined, including areas generally spared by disease. In brain, certain regions (the striatum, for example) express ataxin-3 in only a limited subset of neurons. Immunolocalization studies in normal and disease brain, and in transfected cells, indicate that ataxin-3 is predominantly a cytoplasmic protein that localizes to neuronal processes as well. We conclude that in MJD, as in other polyglutamine repeat diseases, cellular expression of the disease gene is not itself sufficient to cause neuronal degeneration; other cell-specific factors must be invoked to explain the restricted neuropathology seen in MJD. The restricted expression of ataxin-3 in certain regions, however, may influence the pattern of neurodegeneration and provide clues to the protein's function.read more
Citations
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Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the hd mutation
Stephen W. Davies,Mark Turmaine,Barbara A. Cozens,Marian DiFiglia,Alan H. Sharp,Christopher A. Ross,Eberhard Scherzinger,Erich E. Wanker,Laura Mangiarini,Gillian P. Bates +9 more
TL;DR: In this paper, the authors observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to 157 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype.
Journal ArticleDOI
Intranuclear Inclusions of Expanded Polyglutamine Protein in Spinocerebellar Ataxia Type 3
Henry L. Paulson,Matthew K. Perez,Yvon Trottier,John Q. Trojanowski,S. H. Subramony,S.S Das,Parminder J. S. Vig,Jean-Louis Mandel,Kenneth H. Fischbeck,Randall N. Pittman +9 more
TL;DR: It is suggested that intranuclear aggregation of the expanded protein is a unifying feature of CAG/polyglutamine diseases and may be initiated or catalyzed by a glutamine-containing fragment of the disease protein.
Journal ArticleDOI
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.
Journal ArticleDOI
Huntingtin aggregation and toxicity in Huntington's disease.
TL;DR: It is demonstrated that preformed polyQ aggregates are highly toxic when directed to the cell nucleus, consistent with aggregate toxicity, and further validates polyQ aggregation as a therapeutic target.
Journal ArticleDOI
Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers.
Claudia M. Greco,Randi J Hagerman,Flora Tassone,Albert E. Chudley,M. R. Del Bigio,Sébastien Jacquemont,Maureen A. Leehey,Paul J. Hagerman +7 more
TL;DR: The presence of inclusions in the brains of all four FXS carriers with the neurological findings provides further support for a unique clinical entity associated with pre-mutation FMR1 alleles.
References
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A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
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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
Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.
TL;DR: It is concluded that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of X-LINKED spinal and bulbar muscular atrophy.