Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells
Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells
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DOI：
10.1093/hmg/9.19.2799
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发表时间：
2000-11-22
影响因子：
3.5
通讯作者：
MacDonald, ME
中科院分区：
文献类型：
--
作者：
Trettel, F;Rigamonti, D;MacDonald, ME
延长亨廷顿蛋白中的谷氨酰胺束会导致亨廷顿病(HD)患者纹状体神经元的退化。为了确定突变蛋白功能异常的候选途径，我们比较了从野生型和HDH(Q111)敲入胚胎建立的纹状体细胞系。全长亨廷顿蛋白的替代版本因表位可及性而异，定位于参与RNA生物发生和膜运输的不同核和核周细胞器，然而，突变的STHdh(Q111)细胞也显示出额外形式的全长突变蛋白，并显示出显性表型，不反映亨廷顿蛋白缺乏或过剩引起的表型。这些表型表明，突变蛋白通过一种独立于其正常活动的机制破坏了纹状体细胞的动态平衡。它们还支持特定的应激途径，包括P53升高、内质网应激反应和低氧，作为HD的潜在参与者。
Lengthening a glutamine tract in huntingtin confers a dominant attribute that initiates degeneration of striatal neurons in Huntington's disease (HD). To identify pathways that ave candidates for the mutant protein's abnormal function, we compared striatal cell lines established from wild-type and Hdh(Q111) knock-in embryos. Alternate versions of full-length huntingtin, distinguished by epitope accessibility, were localized to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking, However, mutant STHdh(Q111) cells also exhibited additional forms of the full-length mutant protein and displayed dominant phenotypes that did not mirror phenotypes caused by either huntingtin deficiency or excess. These phenotypes; indicate a disruption of striatal cell homeostasis by the mutant protein, via a mechanism that is separate front its normal activity. They also support specific stress pathways, including elevated p53, endoplasmic reticulum stress response and hypoxia, as potential players in HD.