Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1.

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.

journal_name

Nat Genet

journal_title

Nature genetics

authors

Cummings CJ,Mancini MA,Antalffy B,DeFranco DB,Orr HT,Zoghbi HY

doi

10.1038/502

subject

Has Abstract

pub_date

1998-06-01 00:00:00

pages

148-54

issue

2

eissn

1061-4036

issn

1546-1718

journal_volume

19

pub_type

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