Abnormal accumulation of α-synuclein and mitochondria dynamics dysfunction are considered to be implicated in the pathogenesis of Parkinson's disease. However, the underlying mechanisms how α-synuclein abnormal accumulation causes mitochondrial dynamics dysfunction remains unclear. Here, we demonstrate that dynamin-related protein 1(DRP1) is a substrate for p38 MAPK, mutant α-synuclein overexpression in SN4741 cell caused p38 MAPK activation, p38 MAPK-mediated phosphorylation DRP1 at serine 616 to activate DRP1 and is associated with increased mitochondrial fission, which resulted in mitochondrial dysfunction and neuronal loss. Inhibition of p38 MAPK or expression of a kinase death form of p38 MAPK not only attenuates DRP1-mediated mitochondrial fission，but also restores the mitochondrial dysfunction and cell death in α-synuclein A53T model. These findings showed that inhibition of p38 MAPK-DRP1 signaling pathway may be a viable therapeutic strategy of PD on maintenance of mitochondrial homeostasis.

中文翻译：

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p38 MAPK-DRP1信号传导与帕金森氏病突变型A53Tα-突触核蛋白模型中的线粒体功能障碍和细胞死亡有关。

α-突触核蛋白的异常积累和线粒体动力学功能障碍被认为与帕金森氏病的发病机理有关。但是，尚不清楚α-突触核蛋白异常积累如何引起线粒体动力学功能障碍的潜在机制。在这里，我们证明了dynamin相关蛋白1（DRP1）是p38 MAPK的底物，突变的α-突触核蛋白在SN4741细胞中的过度表达导致p38 MAPK激活，p38 MAPK介导的丝氨酸616磷酸化DRP1激活DRP1，并与增加线粒体裂变，导致线粒体功能障碍和神经元丢失。p38 MAPK的抑制或p38 MAPK激酶死亡形式的表达不仅减弱了DRP1介导的线粒体裂变，而且还恢复了α-突触核蛋白A53T模型中的线粒体功能障碍和细胞死亡。