Nucifora F C, Sasaki M, Peters M F, Huang H, Cooper J K, Yamada M, Takahashi H, Tsuji S, Troncoso J, Dawson V L, Dawson T M, Ross C A
Division of Neurobiology, Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
Science. 2001 Mar 23;291(5512):2423-8. doi: 10.1126/science.1056784.
Expanded polyglutamine repeats have been proposed to cause neuronal degeneration in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short polyglutamine tracts such as the transcriptional coactivator CREB binding protein, CBP. We found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain. Expanded polyglutamine repeats specifically interfere with CBP-activated gene transcription, and overexpression of CBP rescued polyglutamine-induced neuronal toxicity. Thus, polyglutamine-mediated interference with CBP-regulated gene transcription may constitute a genetic gain of function, underlying the pathogenesis of polyglutamine disorders.
多聚谷氨酰胺重复序列的扩展被认为会导致亨廷顿舞蹈病（HD）及相关疾病中的神经元变性，其机制是通过与其他含有短多聚谷氨酰胺序列的蛋白质发生异常相互作用，比如转录共激活因子CREB结合蛋白（CBP）。我们发现，在HD细胞培养模型、HD转基因小鼠以及人类HD患者的尸检脑组织中，CBP从其正常的核定位中被耗尽，并存在于多聚谷氨酰胺聚集体中。扩展的多聚谷氨酰胺重复序列特异性地干扰CBP激活的基因转录，而CBP的过表达可挽救多聚谷氨酰胺诱导的神经元毒性。因此，多聚谷氨酰胺介导的对CBP调控基因转录的干扰可能构成一种功能获得性遗传，这是多聚谷氨酰胺疾病发病机制的基础。
