Cummings C J, Mancini M A, Antalffy B, DeFranco D B, Orr H T, Zoghbi H Y
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Nat Genet. 1998 Jun;19(2):148-54. doi: 10.1038/502.
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.
1型脊髓小脑共济失调（SCA1）是一种常染色体显性神经退行性疾病，由ataxin-1中多聚谷氨酰胺序列的扩增引起。在SCA1患者和转基因小鼠的受影响神经元中，突变型ataxin-1聚集在单个泛素阳性核内包涵体中。在本研究中，我们发现这些包涵体对20S蛋白酶体和分子伴侣HDJ-2/HSDJ呈阳性染色。同样，用突变型ataxin-1转染的HeLa细胞形成与20S蛋白酶体和内源性HDJ-2/HSDJ共定位的核聚集体。野生型HDJ-2/HSDJ在HeLa细胞中的过表达降低了ataxin-1聚集的频率。这些数据表明，蛋白质错误折叠是SCA1中所见核聚集体的原因，并且DnaJ伴侣的过表达促进了对错误折叠的多聚谷氨酰胺重复蛋白的识别，从而使其重新折叠和/或进行泛素依赖性降解。
