Bae Byoung-Il, Hara Makoto R, Cascio Matthew B, Wellington Cheryl L, Hayden Michael R, Ross Christopher A, Ha Hyo Chol, Li Xiao-Jiang, Snyder Solomon H, Sawa Akira
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3405-9. doi: 10.1073/pnas.0511316103. Epub 2006 Feb 21.
The pathophysiology of Huntington's disease reflects actions of mutant Huntingtin (Htt) (mHtt) protein with polyglutamine repeats, whose N-terminal fragment translocates to the nucleus to elicit neurotoxicity. We establish that the nuclear translocation and associated cytotoxicity of mHtt reflect a ternary complex of mHtt with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of GAPDH or Siah1 enhances nuclear translocation of mHtt and cytotoxicity, whereas GAPDH mutants that cannot bind Siah1 prevent translocation. Depletion of GAPDH or Siah1 by RNA interference diminishes nuclear translocation of mHtt.
亨廷顿舞蹈症的病理生理学反映了具有多聚谷氨酰胺重复序列的突变型亨廷顿蛋白(mHtt)的作用,其N端片段易位至细胞核引发神经毒性。我们证实,mHtt的核易位及相关细胞毒性反映了mHtt与甘油醛-3-磷酸脱氢酶(GAPDH)及泛素-E3连接酶Siah1形成的三元复合物。GAPDH或Siah1的过表达增强了mHtt的核易位及细胞毒性,而无法结合Siah1的GAPDH突变体则可阻止易位。通过RNA干扰耗尽GAPDH或Siah1可减少mHtt的核易位。