Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Neuropharmacology. 2011 Jun;60(7-8):1187-92. doi: 10.1016/j.neuropharm.2010.10.025. Epub 2010 Oct 31.
Despite identification of the gene for huntingtin (Htt) as causal in Huntington's Disease (HD), explication of HD symptoms and selective damage to the corpus striatum has been elusive. The small G protein Rhes Ras homolog enriched in striatum, highly localized to the striatum, binds selectively to mutant Htt (mHtt) and enhances sumoylation of mHtt. Sumoylation disaggregates mHtt and augments its cytotoxicity. Thus, it appears likely that Rhes-mHtt interaction accounts in substantial part for the selective striatal neurotoxicity of HD with associated extrapyramidal symptomatology. Rhes also binds and activates mTOR, enhancing its influence on protein synthesis, and may be the principal determinant of striatal mTOR activation. In HD, sequestration of Rhes by mHtt may decrease its access to mTOR. The attendant loss of protein translational stimulation may explain the pronounced striatal atrophy of HD. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
尽管亨廷顿病（HD）的致病基因已被确定为 huntingtin（Htt），但对 HD 症状的解释和对纹状体的选择性损伤仍难以捉摸。富含纹状体的小 G 蛋白 Rhes Ras 同源物高度定位于纹状体，选择性结合突变型 Htt（mHtt）并增强 mHtt 的 sumoylation。Sumoylation 可使 mHtt 解聚并增强其细胞毒性。因此，Rhes-mHtt 相互作用似乎很可能在很大程度上解释了 HD 的选择性纹状体神经毒性及其相关的锥体外系症状。Rhes 还结合并激活 mTOR，增强其对蛋白质合成的影响，并且可能是纹状体 mTOR 激活的主要决定因素。在 HD 中，mHtt 将 Rhes 隔离可能会降低其与 mTOR 的接触。随之而来的蛋白质翻译刺激的丧失可能解释了 HD 明显的纹状体萎缩。本文是题为“神经药理学趋势：纪念 Erminio Costa”的特刊的一部分。
