Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion
Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion
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亨廷顿蛋白是神经发生所必需的，不会因亨廷顿氏病的 CAG 扩增而受损
DOI：
10.1038/ng1297-404
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发表时间：
1997-12-01
期刊：
影响因子：
30.8
通讯作者：
MacDonald, ME
中科院分区：
文献类型：
--
作者：
White, JK;Auerbach, W;MacDonald, ME
亨廷顿氏病（HD）是一种常染色体显性遗传的神经退行性疾病，其由CAG重复序列扩增引起，CAG重复序列扩增延长了新型亨廷顿蛋白中的谷氨酰胺片段。为了阐明HD的分子基础，我们通过靶向引入扩展的人HD CAG重复序列，扩展了小鼠同源物Hdh的多聚谷氨酰胺束，从而产生突变型Hdh（neoQ50）和Hdh（Q50）等位基因，其分别表达降低和野生型水平的改变的亨廷顿蛋白。水平降低的纯合子小鼠表现出特征性的异常脑发育和围产期致死性，表明Hdh在神经发生中的关键功能。然而，具有正常水平的突变亨廷顿蛋白的小鼠没有显示出这些异常，表明扩增的CAG重复不会消除或可检测地损害亨廷顿蛋白的神经原性功能。因此，人类的HD缺陷并不模拟完全或部分Hdh失活，并且似乎通过功能获得机制引起神经退行性疾病。
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion that lengthens a glutamine segment in the novel huntingtin protein. To elucidate the molecular basis of HD, we extended the polyglutamine tract of the mouse homologue, Hdh, by targetted introduction of an expanded human HD CAG repeat, creating mutant Hdh(neoQ50) and Hdh(Q50) alleles that express reduced and wildtype levels of altered huntingtin, respectively. Mice homozygous for reduced levels displayed characteristic aberrant brain development and perinatal lethality, indicating a critical function for Hdh in neurogenesis. However, mice with normal levels of mutant huntingtin did not display these abnormalities, indicating that the expanded CAG repeat does not eliminate or detectably impair huntingtin's neurogenic function. Thus, the HD defect in man does not mimic complete or partial Hdh inactivation and appears to cause neurodegenerative disease by a gain-of-function mechanism.