ATAXIN-1 interacts with the repressor capicua in its native complex to cause SCA1 neuropathology
ATAXIN-1 interacts with the repressor capicua in its native complex to cause SCA1 neuropathology
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DOI：
10.1016/j.cell.2006.11.038
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发表时间：
2006-12-29
期刊：
影响因子：
64.5
通讯作者：
Zoghbi, Huda Y.
中科院分区：
文献类型：
--
作者：
Lam, Yung C.;Bowman, Aaron B.;Zoghbi, Huda Y.
脊髓小脑型共济失调1型(SCA1)是由疾病蛋白中多聚谷氨酰胺束扩张引起的几种神经退行性疾病之一，在本例中为ATAXIN-1(ATXN1)。该领域的一个关键问题是，神经毒性是通过与扩展蛋白的异常、新颖的相互作用介导的，还是其野生型功能被增强到有害的程度。我们研究了小鼠小脑中的可溶性蛋白质复合体，发现大多数野生型和扩展的ATXN1组装成包含转录抑制因子Capicua的大型稳定复合体。ATXN1直接与Capicua结合并调节果蝇和哺乳动物细胞中Capicua的阻遏活性，其缺失降低了Capicua的稳态水平。有趣的是，S776A突变消除了扩展的ATXN1的神经毒性，在体内大大减少了突变ATXN1与Capicua的联系。这些数据提供了对ATXN1功能的洞察，并表明SCA1神经病理依赖于天然的，而不是新的蛋白质相互作用。
Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative diseases caused by expansion of a polyglutamine tract in the disease protein, in this case, ATAXIN-1 (ATXN1). A key question in the field is whether neurotoxicity is mediated by aberrant, novel interactions with the expanded protein or whether its wild-type functions are augmented to a deleterious degree. We examined soluble protein complexes from mouse cerebellum and found that the majority of wild-type and expanded ATXN1 assembles into large stable complexes containing the transcriptional repressor Capicua. ATXN1 directly binds Capicua and modulates Capicua repressor activity in Drosophila and mammalian cells, and its loss decreases the steady-state level of Capicua. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded ATXN1, substantially reduces the association of mutant ATXN1 with Capicua in vivo. These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions.