Huntingtin-Encoded Polyglutamine Expansions Form Amyloid-like Protein Aggregates In Vitro and In Vivo
Eberhard Scherzinger,Rudi Lurz,Mark Turmaine,Laura Mangiarini,Birgit Hollenbach,Renate Hasenbank,Gillian P. Bates,Stephen W. Davies,Hans Lehrach,Erich E. Wanker +9 more
TLDR
In this study, it is shown that the proteolytic cleavage of a GST-huntingtin fusion protein leads to the formation of insoluble high molecular weight protein aggregates only when the polyglutamine expansion is in the pathogenic range.About:
This article is published in Cell.The article was published on 1997-08-08 and is currently open access. It has received 1295 citations till now. The article focuses on the topics: Polyglutamine tract & Huntingtin.read more
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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.
Journal ArticleDOI
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
Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death
TL;DR: It is shown, by survival analysis, that neurons die in a time-independent fashion but one that is dependent on mutant huntingtin dose and polyglutamine expansion; many neurons die without forming an inclusion body.
Journal ArticleDOI
Apoptosis in the nervous system
Junying Yuan,Bruce A. Yankner +1 more
TL;DR: The principal molecular components of the apoptosis programme in neurons include Apaf-1 (apoptotic protease-activating factor 1) and proteins of the Bcl-2 and caspase families, which regulate neuronal apoptosis through the action of critical protein kinase cascades.
Journal ArticleDOI
Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders.
Byron Caughey,Peter T. Lansbury +1 more
TL;DR: Recent biophysical studies aimed at elucidating the precise mechanism of in vitro aggregation and animal modeling studies support the emerging notion that an ordered prefibrillar oligomer, or protofibril, may be responsible for cell death and that the fibril form that is typically observed at autopsy may actually be neuroprotective.
References
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Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications.
TL;DR: A method has been devised for the electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets that results in quantitative transfer of ribosomal proteins from gels containing urea.
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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
Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase.
D B Smith,Kevin S. Johnson +1 more
TL;DR: Plasmid expression vectors have been constructed that direct the synthesis of foreign polypeptides in Escherichia coli as fusions with the C terminus of Sj26, a 26-kDa glutathione S-transferase (GST; EC 2.5.1.18) encoded by the parasitic helminth Schistosoma japonicum.
Journal ArticleDOI
Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice
Laura Mangiarini,Kirupa Sathasivam,Mary J. Seller,Barbara A. Cozens,Alex Harper,Colin Hetherington,Martin Lawton,Yvon Trottier,Hans Lehrach,Stephen W. Davies,Gillian P. Bates +10 more
TL;DR: Mice have been generated that are transgenic for the 5' end of the human HD gene carrying CAG/polyglutamine repeat expansion that exhibits many of the features of HD, including choreiform-like movements, involuntary stereotypic movements, tremor, and epileptic seizures.
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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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