DJ-1 Protects Dopaminergic Neurons against Rotenone-Induced Apoptosis by Enhancing ERK-Dependent Mitophagy
DJ-1 Protects Dopaminergic Neurons against Rotenone-Induced Apoptosis by Enhancing ERK-Dependent Mitophagy
复制标题
DJ-1 通过增强 ERK 依赖性线粒体自噬保护多巴胺能神经元免受鱼藤酮诱导的细胞凋亡
DOI：
10.1016/j.jmb.2012.06.034
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发表时间：
2012-10-19
影响因子：
5.6
通讯作者：
Yang, H.
中科院分区：
文献类型：
--
作者：
Gao, H.;Yang, W.;Yang, H.
编码多功能蛋白DJ-1的基因中的功能缺失突变与早发性家族性帕金森病（PD）的发病机制有关，这表明DJ-1可能作为多巴胺能（DA）神经元的神经保护剂。增强的自噬可能通过清除受损的细胞器和蛋白质聚集体而有益于PD;因此，我们确定DJ-1是否通过自噬途径保护DA神经元免受线粒体功能障碍和氧化应激。用线粒体复合物I抑制剂鱼藤酮处理过表达DJ-1的培养DA细胞（MN 9D）。此外，在注射DJ-1表达载体4周后，将鱼藤酮注射到大鼠的左侧黑质中。DJ-1的过表达保护MN 9D细胞免于凋亡，显著增强了体内鱼藤酮处理后黑质DA神经元的存活，并挽救了大鼠的行为异常。过表达的DJ-1增强鱼藤酮诱发的自噬标志物，beclin-1和LC 3 II的表达，而透射电子显微镜和共聚焦成像显示，超微结构的迹象，自噬增加DJ-1。DJ-1的神经保护作用被磷酸肌醇激酶和自噬抑制剂3-甲基腺嘌呤以及ERK途径抑制剂U 0126阻断。共聚焦成像显示，在鱼藤酮处理后12小时，在DJ-1过表达的MN 9D细胞中，p62阳性斑点的大小显著减小，这表明DJ-1揭示了清除与PD相关的聚集的p62的能力。控制自噬的因子，包括DJ-1，可能抑制鱼藤酮诱导的细胞凋亡，并为PD的治疗干预提供新的靶点。(C)2012爱思唯尔有限公司出版
Loss-of-function mutations in the gene encoding the multifunctional protein, DJ-1, have been implicated in the pathogenesis of early-onset familial Parkinson's disease (PD), suggesting that DJ-1 may act as a neuroprotectant for dopaminergic (DA) neurons. Enhanced autophagy may benefit PD by clearing damaged organelles and protein aggregates; thus, we determined if DJ-1 protects DA neurons against mitochondrial dysfunction and oxidative stress through an autophagic pathway. Cultured DA cells (MN9D) overexpressing DJ-1 were treated with the mitochondrial complex I inhibitor, rotenone. In addition, rotenone was injected into the left substantia nigra of rats 4 weeks after injection with a DJ-1 expression vector. Overexpression of DJ-1 protected MN9D cells against apoptosis, significantly enhanced the survival of nigral DA neurons after rotenone treatment in vivo, and rescued rat behavioral abnormalities. Overexpression of DJ-1 enhanced rotenone-evoked expression of the autophagic markers, beclin-1 and LC3II, while transmission electron microscopy and confocal imaging revealed that the ultrastructural signs of autophagy were increased by DJ-1. The neuroprotective effects of DJ-1 were blocked by phosphoinositol kinase and the autophagy inhibitor, 3-methyladenine, and by the ERK pathway inhibitor, U0126. Confocal imaging revealed that the size of p62-positive puncta decreased significantly in DJ-1 overexpression of MN9D cells 12h after rotenone treatment, suggesting that DJ-1 reveals the ability to clear aggregated p62 associated with PD. Factors that control autophagy, including DJ-1, may inhibit rotenone-induced apoptosis and present novel targets for therapeutic intervention in PD. (C) 2012 Published by Elsevier Ltd.