ROCK1 induces dopaminergic nerve cell apoptosis via the activation of Drp1-mediated aberrant mitochondrial fission in Parkinson's disease
ROCK1 induces dopaminergic nerve cell apoptosis via the activation of Drp1-mediated aberrant mitochondrial fission in Parkinson's disease
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ROCK1 通过激活 Drp1 介导的帕金森病线粒体异常裂变诱导多巴胺能神经细胞凋亡
DOI：
10.1038/s12276-019-0318-z
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发表时间：
2019
影响因子：
12.8
通讯作者：
Zhang Rong
中科院分区：
文献类型：
--
作者：
Zhang Qian;Hu Changpeng;Huang Jingbin;Liu Wuyi;Lai Wenjing;Leng Faning;Tang Qin;Liu Yali;Wang Qing;Zhou Min;Sheng Fangfang;Li Guobing;Zhang Rong
多巴胺缺乏主要是由中脑黑质和纹状体多巴胺能神经细胞凋亡引起，是帕金森病（PD）的重要病理基础。最近的研究表明，动力相关蛋白 1 (Drp1) 介导的异常线粒体分裂在多巴胺能神经细胞凋亡中起着至关重要的作用。但上游监管机制尚不明确。我们的研究表明 Drp1 敲低可抑制异常线粒体裂变和细胞凋亡。重要的是，我们发现 ROCK1 在 MPP+ 诱导的 PD 细胞模型中被激活，并且 ROCK1 敲低和特异性 ROCK1 激活抑制剂 Y-27632 通过抑制 Drp1 去磷酸化/激活来阻断 Drp1 介导的异常线粒体裂变和多巴胺能神经细胞凋亡。我们的体内研究证实，Y-27632 通过抑制 Drp1 介导的异常线粒体裂变和细胞凋亡，显着改善 PD 小鼠模型的症状。总的来说，我们的研究结果表明 PD 发病机制的一个重要分子机制涉及 ROCK1 通过激活 Drp1 诱导的异常线粒体裂变来调节多巴胺能神经细胞凋亡。
Dopamine deficiency is mainly caused by apoptosis of dopaminergic nerve cells in the substantia nigra of the midbrain and the striatum and is an important pathologic basis of Parkinson’s disease (PD). Recent research has shown that dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission plays a crucial role in dopaminergic nerve cell apoptosis. However, the upstream regulatory mechanism remains unclear. Our study showed that Drp1 knockdown inhibited aberrant mitochondrial fission and apoptosis. Importantly, we found that ROCK1 was activated in an MPP+-induced PD cell model and that ROCK1 knockdown and the specific ROCK1 activation inhibitor Y-27632 blocked Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cells by suppressing Drp1 dephosphorylation/activation. Our in vivo study confirmed that Y-27632 significantly improved symptoms in a PD mouse model by inhibiting Drp1-mediated aberrant mitochondrial fission and apoptosis. Collectively, our findings suggest an important molecular mechanism of PD pathogenesis involving ROCK1-regulated dopaminergic nerve cell apoptosis via the activation of Drp1-induced aberrant mitochondrial fission.