Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease
Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease
复制标题
DOI：
10.1523/jneurosci.5927-11.2012
复制
发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Kourosh Shahpasand;I. Uemura;Taro Saito;T. Asano;K. Hata;Keitaro Shibata;Y. Toyoshima;M. Hasegawa;S. Hisanaga
中科院分区：
文献类型：
--
作者：
Kourosh Shahpasand;I. Uemura;Taro Saito;T. Asano;K. Hata;Keitaro Shibata;Y. Toyoshima;M. Hasegawa;S. Hisanaga
微管相关蛋白Tau是作为阿尔茨海默病的神经病理学标志的神经元缠结的主要成分。Tau是蛋白质在多个位点磷酸化的底物，并且以过度磷酸化状态缠结。然而，Tau磷酸化的生理功能或它如何可能有助于阿尔茨海默病的病理生理机制尚未完全了解。在这里，我们研究了人类Tau蛋白磷酸化在三个位点的功能，Ser199，Ser202和Thr205，它们共同构成了标记阿尔茨海默病异常磷酸化的AT8位点。野生型Tau或突变形式的过表达，其中这些网站已被改变为不可磷酸化的丙氨酸或磷酸模拟谷氨酸抑制PC12细胞以及小鼠大脑皮层神经元的轴突突起的线粒体运动。然而，对线粒体易位的最大影响是由拟磷酸化突变引起的。当细胞膜张力通过破坏肌动蛋白丝而降低时，这些突变也会导致培养细胞中微管之间的空间扩大。因此，AT8位点的Tau磷酸化可能对线粒体运动具有有意义的影响，可能是通过控制微管间距。AT8位点的过度磷酸化可能通过破坏阿尔茨海默病中的线粒体转运而导致轴突变性。
The microtubule-associated protein Tau is a major component of the neurofibrillary tangles that serve as a neuropathological hallmark of Alzheimer's disease. Tau is a substrate for protein phosphorylation at multiple sites and occurs in tangles in a hyperphosphorylated state. However, the physiological functions of Tau phosphorylation or how it may contribute mechanistically to Alzheimer's pathophysiology are not completely understood. Here, we examined the function of human Tau phosphorylation at three sites, Ser199, Ser202, and Thr205, which together comprise the AT8 sites that mark abnormal phosphorylation in Alzheimer's disease. Overexpression of wild-type Tau or mutated forms in which these sites had been changed to either unphosphorylatable alanines or phosphomimetic aspartates inhibited mitochondrial movement in the neurite processes of PC12 cells as well as the axons of mouse brain cortical neurons. However, the greatest effects on mitochondrial translocation were induced by phosphomimetic mutations. These mutations also caused expansion of the space between microtubules in cultured cells when membrane tension was reduced by disrupting actin filaments. Thus, Tau phosphorylation at the AT8 sites may have meaningful effects on mitochondrial movement, likely by controlling microtubule spacing. Hyperphosphorylation of the AT8 sites may contribute to axonal degeneration by disrupting mitochondrial transport in Alzheimer's disease.