BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival
BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival
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DOI：
10.1074/jbc.m115.677815
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发表时间：
2015-12-18
影响因子：
4.8
通讯作者：
Park, David S.
中科院分区：
文献类型：
--
作者：
Qu, Dianbo;Hage, Ali;Park, David S.
新出现的证据表明，帕金森病（PD）的遗传成分越来越多。例如，PINK 1或PARKIN的功能缺失突变可导致常染色体隐性PD。最近，PINK 1和PARKIN已经被牵涉到相同的信号传导途径中，通过在去极化线粒体的外膜上稳定PINK 1来募集PARKIN来调节线粒体清除。控制这一过程的确切机制仍然是个谜。在这项研究中，我们确定Bcl 2相关的athanogene 2（BAG 2）作为一个因素，促进线粒体自噬。BAG 2通过阻断泛素化途径抑制PINK 1降解。在PD的体外细胞模型中，通过BAG 2稳定PINK 1触发PARKIN介导的线粒体自噬并保护神经元免受1-甲基-4-苯基吡啶诱导的氧化应激。总的来说，我们的研究结果支持BAG 2是PINK 1/PARKIN信号通路的上游调节因子的观点。
Emerging evidence has demonstrated a growing genetic component in Parkinson disease (PD). For instance, loss-of-function mutations in PINK1 or PARKIN can cause autosomal recessive PD. Recently, PINK1 and PARKIN have been implicated in the same signaling pathway to regulate mitochondrial clearance through recruitment of PARKIN by stabilization of PINK1 on the outer membrane of depolarized mitochondria. The precise mechanisms that govern this process remain enigmatic. In this study, we identify Bcl2-associated athanogene 2 (BAG2) as a factor that promotes mitophagy. BAG2 inhibits PINK1 degradation by blocking the ubiquitination pathway. Stabilization of PINK1 by BAG2 triggers PARKIN-mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of PD. Collectively, our findings support the notion that BAG2 is an upstream regulator of the PINK1/PARKIN signaling pathway.