Hong Sunghoi, Kim Sung-Jo, Ka Sojeong, Choi Inho, Kang Seongman
Graduate School of Biotechnology, Korea University, 1,5-ka Anam-dong, Sungbuk-ku, Seoul 136-701, Korea.
Mol Cell Neurosci. 2002 Jun;20(2):298-306. doi: 10.1006/mcne.2002.1103.
Spinocerebellar ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder characterized by ataxia and progressive motor deterioration. SCA1 has been known to associate with elongated polyglutamine tract in ataxin-1, the SCA1 gene product. Using the yeast two-hybrid system, we have found that USP7, a ubiquitin-specific protease, binds to ataxin-1. Further experiments with deletion mutants indicated that the C-terminal region of ataxin-1 was essential for the interaction. Liquid beta-galactosidase assay and coimmunoprecipitation experiments revealed that the strength of the interaction between USP7 and ataxin-1 is influenced by the length of the polyglutamine tract in the ataxin-1; weaker interaction was observed in mutant ataxin-1 with longer polyglutamine tract and USP7 was not recruited to the mutant ataxin-1 aggregates in the Purkinje cells of SCA1 transgenic mice. Our results suggest that altered function of the ubiquitin system can be involved in the pathogenesis of spinocerebellar ataxia type 1.
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，其特征为共济失调和进行性运动功能衰退。已知SCA1与SCA1基因产物ataxin-1中延长的聚谷氨酰胺序列相关。利用酵母双杂交系统，我们发现泛素特异性蛋白酶USP7与ataxin-1结合。对缺失突变体进行的进一步实验表明，ataxin-1的C末端区域对于这种相互作用至关重要。液体β-半乳糖苷酶分析和免疫共沉淀实验显示，USP7与ataxin-1之间相互作用的强度受ataxin-1中聚谷氨酰胺序列长度的影响；在聚谷氨酰胺序列较长的突变型ataxin-1中观察到较弱的相互作用，并且在SCA1转基因小鼠的浦肯野细胞中，USP7未被募集到突变型ataxin-1聚集体中。我们的结果表明，泛素系统功能改变可能参与1型脊髓小脑共济失调的发病机制。
