Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1.
Nat Genet
; 19(2): 148-54, 1998 Jun.
Article
em En
| MEDLINE
| ID: mdl-9620770
ABSTRACT
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine tract in ataxin-1. In affected neurons of SCA1 patients and transgenic mice, mutant ataxin-1 accumulates in a single, ubiquitin-positive nuclear inclusion. In this study, we show that these inclusions stain positively for the 20S proteasome and the molecular chaperone HDJ-2/HSDJ. Similarly, HeLa cells transfected with mutant ataxin-1 develop nuclear aggregates which colocalize with the 20S proteasome and endogenous HDJ-2/HSDJ. Overexpression of wild-type HDJ-2/HSDJ in HeLa cells decreases the frequency of ataxin-1 aggregation. These data suggest that protein misfolding is responsible for the nuclear aggregates seen in SCA1, and that overexpression of a DnaJ chaperone promotes the recognition of a misfolded polyglutamine repeat protein, allowing its refolding and/or ubiquitin-dependent degradation.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cisteína Endopeptidases
/
Proteínas Nucleares
/
Degenerações Espinocerebelares
/
Dobramento de Proteína
/
Chaperonas Moleculares
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Complexos Multienzimáticos
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Proteínas do Tecido Nervoso
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Genet
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
1998
Tipo de documento:
Article
País de afiliação:
Estados Unidos