p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease
p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease
复制标题
DOI：
10.1016/j.neuron.2005.06.005
复制
发表时间：
2005-07-07
期刊：
影响因子：
16.2
通讯作者：
Sawa, A
中科院分区：
文献类型：
--
作者：
Bae, BI;Xu, H;Sawa, A
我们提供了 p53 在亨廷顿病 (HD) 线粒体相关细胞功能障碍和行为异常中的特定作用的证据。具有扩展的聚谷氨酰胺 (polyQ) 的突变亨廷顿蛋白 (mHtt) 与 p53 结合并上调核 p53 水平以及神经元培养物中的 p53 转录活性。这种增强是特异性的，因为它发生在 mHtt 中，而不是带有扩展的 polyQ 的突变 ataxin-1。 mHtt 转基因 (mHtt-Tg) 小鼠和 HD 患者大脑中的 p53 水平也有所增加。 Pifithrin-α、RNA 干扰或基因缺失对 p53 的扰动可防止 HD 细胞中线粒体膜去极化和细胞毒性，以及 mHtt-Tg 小鼠呼吸复合物 IV 活性的降低。 p53 的基因缺失可抑制 mHtt-Tg 果蝇的神经变性和 mHtt-Tg 小鼠的神经行为异常。我们的研究结果表明 p53 与 HD 的核和线粒体病理特征有关。
We present evidence for a specific role of p53 in the mitochondria-associated cellular dysfunction and behavioral abnormalities of Huntington's disease (HD). Mutant huntingtin (mHtt) with expanded polyglutamine (polyQ) binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity in neuronal cultures. The augmentation is specific, as it occurs with mHtt but not mutant ataxin-1 with expanded polyQ. p53 levels are also increased in the brains of mHtt transgenic (mHtt-Tg) mice and HD patients. Perturbation of p53 by pifithrin-alpha, RNA interference, or genetic deletion prevents mitochondrial membrane depolarization and cytotoxicity in HD cells, as well as the decreased respiratory complex IV activity of mHtt-Tg mice. Genetic deletion of p53 suppresses neurodegeneration in mHtt-Tg flies and neurobehavioral abnormalities of mHtt-Tg mice. Our findings suggest that p53 links nuclear and mitochondrial pathologies characteristic of HD.