Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1

被引:296
作者
Lin, X
Antalffy, B
Kang, D
Orr, HT
Zoghbi, HY
机构
[1] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA
[4] Univ Minnesota, Inst Human Genet, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA
关键词
D O I
10.1038/72101
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
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收藏
页码:157 / 163
页数:7
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