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Titolo:
Amyloid formation by mutant huntingtin: Threshold, progressivity and recruitment of normal polyglutamine proteins
Autore:
Huang, CC; Faber, PW; Persichetti, F; Mittal, V; Vonsattel, JP; MacDonald, ME; Gusella, JF;
Indirizzi:
Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA Massachusetts Gen Hosp Charlestown MA USA 02129 Charlestown, MA 02129 USA Massachusetts Gen Hosp, Lab Mol Neuropathol, Charlestown, MA 02129 USA Massachusetts Gen Hosp Charlestown MA USA 02129 Charlestown, MA 02129 USA Cold Spring Harbor Lab, Howard Hughes Med Inst, Cold Spring Harbor, NY 11724 USA Cold Spring Harbor Lab Cold Spring Harbor NY USA 11724 rbor, NY 11724 USA
Titolo Testata:
SOMATIC CELL AND MOLECULAR GENETICS
fascicolo: 4, volume: 24, anno: 1998,
pagine: 217 - 233
SICI:
0740-7750(199807)24:4<217:AFBMHT>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
NEURONAL INTRANUCLEAR INCLUSIONS; DISEASE GENE HOMOLOG; AGGREGATES IN-VITRO; GLUTAMINE REPEATS; NEURODEGENERATIVE DISEASES; TISSUE TRANSGLUTAMINASE; EXPANDED POLYGLUTAMINE; NUCLEAR-LOCALIZATION; EMBRYONIC LETHALITY; CAG REPEATS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
49
Recensione:
Indirizzi per estratti:
Indirizzo: Gusella, JF Massachusetts Gen Hosp, Mol Neurogenet Unit, Bldg 149,13th St,Charlestown, MA 02129 USA Massachusetts Gen Hosp Bldg 149,13th St Charlestown MA USA 02129
Citazione:
C.C. Huang et al., "Amyloid formation by mutant huntingtin: Threshold, progressivity and recruitment of normal polyglutamine proteins", SOM CELL M, 24(4), 1998, pp. 217-233

Abstract

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat encoding a tract of consecutive glutamines near the amino terminus of huntingtin, a large protein of unknown function. It has been proposed that theexpanded polyglutamine stretch confers a new property on huntingtin and thereby causes cell and region-specific neurodegeneration. Genotype-phenotypecorrelations predict that this novel property appears above a threshold length (similar to 38 glutamines), becomes progressively more evident with increasing polyglutamine length, is completely dominant over normal huntingtin and is not appreciably worsened by a double genetic dose in ND homozygotes. Recently, an amino terminal fragment of mutant huntingtin has been foundto form self-initiated fibrillar aggregates in vitro. We have tested the capacity for aggregation to assess whether this property matches the criteria expected for a fundamental role in ND pathogenesis. We find that that in vitro aggregation displays a threshold and progressivity for polyglutamine length remarkably similar to the HD disease process. Moreover the mutant huntingtin amino terminus is capable of recruiting into aggregates normal glutamine tract proteins, such as the amino terminal segments of both normal huntingtin and of TATA-binding protein (TBP). Our examination of in vivo aggregates from HD post-mortem brains indicates that they contain an amino terminal segment of huntingtin of between 179 and 595 residues. They also contain non-huntingtin protein, as evidenced by immunostaining for TBP Interestingly, like the in vitro aggregates, aggregates from ND brain display Congored staining with green birefringence characteristic of amyloid. Our data support the view that the expanded polyglutamine segment confers on huntingtin a new property that plays a determining role in HD pathogenesis and could be a target for treatment. Moreover the new property might have its toxic consequences by interaction with one or more normal polyglutamine-containing proteins essential for the survival of target neurons.

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Documento generato il 20/09/20 alle ore 10:42:25