p45, an ATPase subunit of the 19S proteasome, targets the polyglutamine disease protein ataxin-3 to the proteasome.

Abstract:

:Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by an expansion of the polyglutamine tract near the C-terminus of the MJD-1 gene product, ataxin-3. Ataxin-3 is degraded by the proteasome. However, the precise mechanism of ataxin-3 degradation remains to be elucidated. In this study, we show direct links between ataxin-3 and the proteasome. p45, an ATPase subunit of the 19S proteasome, interacts with ataxin-3 in vitro and stimulates the degradation of ataxin-3 in an in vitro reconstituted degradation assay system. The effect of p45 on ataxin-3 degradation is blocked by MG132, a proteasome inhibitor. In N2a or 293 cells, overexpression of p45 strikingly enhances the clearance of both normal and expanded ataxin-3, but not alpha synuclein or SOD1, implying a functional specificity of p45 in this proteolytic process. The N-terminus of ataxin-3, which serves as a recognition site by p45, is necessary for the proteolytic process of ataxin-3. We also show that other three ATPases of the 19S proteasome, MSS1, p48, and p56 have no effect on ataxin-3 degradation. These data provide evidence that p45 plays an important role in regulating ataxin-3 degradation by the proteasome.

journal_name

J Neurochem

authors

Wang H,Jia N,Fei E,Wang Z,Liu C,Zhang T,Fan J,Wu M,Chen L,Nukina N,Zhou J,Wang G

doi

10.1111/j.1471-4159.2007.04460.x

subject

Has Abstract

pub_date

2007-06-01 00:00:00

pages

1651-61

issue

6

eissn

0022-3042

issn

1471-4159

pii

JNC4460

journal_volume

101

pub_type

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