Parkinson's disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes.
Parkinson's disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes.
复制标题
帕金森病相关突变体 VPS35 通过回收 DLP1 复合物导致线粒体功能障碍。
DOI：
10.1038/nm.3983
复制
发表时间：
2016-01
期刊：
影响因子：
82.9
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Wang W;Wang X;Fujioka H;Hoppel C;Whone AL;Caldwell MA;Cullen PJ;Liu J;Zhu X
线粒体功能障碍是帕金森病（Parkinson disease，PD）发病过程中的一个重要环节，越来越多的证据表明线粒体动力学异常和质量控制异常是其重要的潜在机制。VPS 35基因编码逆转录复合体的关键组分，是与PD相关的第三个常染色体显性基因。然而，VPS 35突变如何导致神经退行性变仍不清楚。在这里，我们证明了PD相关的VPS 35突变导致体外培养的神经元，小鼠黑质神经元在体内，和人成纤维细胞从PD患者轴承D 620 N突变的线粒体片段化和细胞死亡。VPS 35诱导的线粒体缺陷和神经元功能障碍可以通过抑制线粒体分裂来预防。VPS 35突变导致与DLP 1的相互作用增加，从而通过源自于线粒体的囊泡依赖性运输到溶酶体进行降解来增强线粒体DLP 1复合物的周转。重要的是，氧化应激增加了VPS 35-DLP 1相互作用，这在散发性PD病例的大脑中也增加了。这些结果揭示了VPS 35参与线粒体分裂的一种新的细胞机制，其失调可能参与家族性和可能散发性PD的发病机制。
Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson disease (PD) and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, encoding a key component of the retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations may lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo, and in human fibroblasts from PD patient bearing the D620N mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutation caused increased interactions with DLP1 which enhanced mitochondrial DLP1 complex turnover via mitochondria-derived vesicles-dependent trafficking to lysosomes for degradation. Importantly, oxidative stress increased the VPS35–DLP1 interaction which was also increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is likely involved in the pathogenesis of familial, and possibly sporadic, PD.