1998
DOI: 10.1038/502
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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 th… Show more

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Cited by 747 publications
(567 citation statements)
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“…The suppression is particularly striking when HDJ-1, a member of the Hsp40 chaperone family, is overexpressed. Suppression of aggregate formation by Hsp40 has previously been demonstrated in in vitro models of polyglutamine disease (Cummings et al 1998;Chai et al 1999). Hsp40 is a cochaperone for Hsp70 and binds to and stimulates the ATPase activity of Hsp70 (Cyr et al 1994).…”
Section: Discussionmentioning
confidence: 88%
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“…The suppression is particularly striking when HDJ-1, a member of the Hsp40 chaperone family, is overexpressed. Suppression of aggregate formation by Hsp40 has previously been demonstrated in in vitro models of polyglutamine disease (Cummings et al 1998;Chai et al 1999). Hsp40 is a cochaperone for Hsp70 and binds to and stimulates the ATPase activity of Hsp70 (Cyr et al 1994).…”
Section: Discussionmentioning
confidence: 88%
“…Cummings et al (1998) used a cellular model of mutant ataxin-1 aggregation to demonstrate that HDJ-1, HDJ-2 and Hsp70 all colocalized with nuclear inclusions. A similar study found that Hsp90 colocalizes with aggregates of mutant androgen receptor but not aggregates of mutant ataxin-3, also using in vitro models of aggregation (Stenoien et al 1999).…”
Section: Discussionmentioning
confidence: 99%
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“…The first ever report that molecular chaperones could act as potent modulators of protein aggregation in neurodegeneration was demonstrated by Cummings et al (1998) in a cellular model of polyQ disease [28]. The overexpression of the DnaJ protein, DnaJA1, reduced the aggregation of polyglutamine expanded ataxin-1.…”
Section: Hd and Polyq Diseasesmentioning
confidence: 99%
“…Spinocerebellar ataxia is also associated with spinocerebellar ataxia type 1 (SCA1) gene with increased trinucleotide repeat numbers from 39 to 82 in ataxin-1 protein (6-44 in normal controls), as well as with spinocerebellar ataxia type 3 (SCA3) or Machoado-Joseph Disease (MJD) gene with increased trinucleotide repeat numbers from 55 to 84 in ataxin-3 protein (12-40 in normal controls) [10]. Cummings et al demonstrated that ataxin-1 with an expanded polyglutamine track is often misfolded, making it a target for proteosome degradation [11]. Moreover, proteins with an expanded polyglutamine track often aggregate with caspase to cause apoptosis [12].…”
Section: Introductionmentioning
confidence: 99%