Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1
Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1
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DOI：
10.1038/72101
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发表时间：
2000-02-01
影响因子：
25
通讯作者：
Zoghbi, HY
中科院分区：
文献类型：
--
作者：
Lin, X;Antalffy, B;Zoghbi, HY
不稳定CAG重复序列的扩增导致脊髓小脑共济失调1型（SCA 1）和其他几种神经退行性疾病。然而，多聚谷氨酰胺扩增如何使所得蛋白质对神经元有毒仍然是难以捉摸的。假设长的多聚谷氨酰胺束改变基因表达，我们发现SCA 1小鼠中参与信号转导和钙稳态的某些神经元基因顺序下调。这些基因丰富的浦肯野细胞，SCA 1发病的主要网站，而且，他们的下调是由扩展的共济失调蛋白-1介导的，并发生在可检测的病理。类似的下调发生在SCA 1人体组织中。改变的基因表达可能是多聚谷氨酰胺毒性的最早介质。
The expansion of an unstable CAG repeat causes spinocerebellar ataxia type 1 (SCA1) and several other neurodegenerative diseases. How polyglutamine expansions render the resulting proteins toxic to neurons, however, remains elusive. Hypothesizing that long polyglutamine tracts alter gene expression, we found certain neuronal genes involved in signal transduction and calcium homeostasis sequentially downregulated in SCA1 mice. These genes were abundant in Purkinje cells, the primary site of SCA1 pathogenesis; moreover, their downregulation was mediated by expanded ataxin-1 and occured before detectable pathology. Similar downregulation occurred in SCA1 human tissues. Altered gene expression may be the earliest mediator of polyglutamine toxicity.