Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease
Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease
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DOI：
10.1038/ng1362
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发表时间：
2004-06-01
期刊：
影响因子：
30.8
通讯作者：
Rubinsztein, DC
中科院分区：
文献类型：
--
作者：
Ravikumar, B;Vacher, C;Rubinsztein, DC
亨廷顿病是由多聚谷氨酰胺束扩张引起的九种遗传性神经退行性疾病之一。扩增的多聚谷氨酰胺蛋白在细胞内聚集体中异常积累。在这里，我们表明，哺乳动物雷帕霉素靶蛋白（mTOR）被隔离在多聚谷氨酰胺聚集在细胞模型，转基因小鼠和人脑。mTOR的隔离损害其激酶活性并诱导自噬，这是突变亨廷顿蛋白片段的关键清除途径。这保护免受聚谷氨酰胺毒性，因为特异性mTOR抑制剂雷帕霉素减弱了亨廷顿病细胞模型中的亨廷顿蛋白积累和细胞死亡，并且自噬的抑制具有匡威的作用。此外，雷帕霉素在亨廷顿病的果蝇模型中保护神经变性，雷帕霉素类似物CCI-779在亨廷顿病的小鼠模型中改善了四种不同行为任务的表现并减少了聚集体形成。我们的数据为诱导自噬治疗亨廷顿病的潜力提供了原理证明。
Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.