DJ-1 associates with synaptic membranes
DJ-1 associates with synaptic membranes
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DOI：
10.1016/j.nbd.2011.05.014
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发表时间：
2011-09
影响因子：
6.1
通讯作者：
Yukiko Usami;T. Hatano;S. Imai;S. Kubo;Shigeto Sato;S. Saiki;Y. Fujioka;Y. Ohba;Fumiaki Sato;M. Funayama;H. Eguchi;Kaori Shiba;H. Ariga;Jie Shen;N. Hattori
中科院分区：
文献类型：
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作者：
Yukiko Usami;T. Hatano;S. Imai;S. Kubo;Shigeto Sato;S. Saiki;Y. Fujioka;Y. Ohba;Fumiaki Sato;M. Funayama;H. Eguchi;Kaori Shiba;H. Ariga;Jie Shen;N. Hattori
帕金森病(PD)是一种由多巴胺能神经元丢失引起的神经退行性疾病。尽管许多报道表明遗传因素与帕金森病的发病有关，但选择性多巴胺能神经元变性的分子机制仍不清楚。DJ-1是Park7连锁的常染色体隐性遗传型早发性帕金森病的致病基因。大量研究表明，外源性DJ-1定位于线粒体和胞浆中，作为分子伴侣、转录调节因子和细胞保护因子抵抗氧化应激。然而，内源性DJ-1的精确亚细胞定位和功能还不是很清楚。DJ-1基因突变导致神经元变性的机制也仍然知之甚少。免疫细胞化学显示DJ-1在培养细胞和小鼠脑原代神经元中呈点状分布于胞浆和膜结构中。有趣的是，DJ-1与高尔基体蛋白GM130以及突触小泡蛋白如突触素和Rab3A共存。Förster共振能量转移分析表明，在活细胞中，DJ-1的一小部分与突触素相互作用。虽然野生型DJ-1蛋白不需要中间蛋白而直接与膜结合，但致病性DJ-1的L166P突变与突触小泡的结合较少。这些结果表明，DJ-1与包括突触膜在内的膜细胞器结合，发挥其正常的功能。
Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons. Although many reports have suggested that genetic factors are implicated in the pathogenesis of PD, molecular mechanisms underlying selective dopaminergic neuronal degeneration remain unknown. DJ-1 is a causative gene for autosomal recessive form of PARK7-linked early-onset PD. A number of studies have demonstrated that exogenous DJ-1 localizes within mitochondria and the cytosol, and functions as a molecular chaperon, as a transcriptional regulator, and as a cell protective factor against oxidative stress. However, the precise subcellular localization and function of endogenous DJ-1 are not well known. The mechanisms by which mutations in DJ-1 contributes to neuronal degeneration also remain poorly understood. Here we show by immunocytochemistry that DJ-1 distributes to the cytosol and membranous structures in a punctate appearance in cultured cells and in primary neurons obtained from mouse brain. Interestingly, DJ-1 colocalizes with the Golgi apparatus proteins GM130 and the synaptic vesicle proteins such as synaptophysin and Rab3A. Förster resonance energy transfer analysis revealed that a small portion of DJ-1 interacts with synaptophysin in living cells. Although the wild-type DJ-1 protein directly associates with membranes without an intermediary protein, the pathogenic L166P mutation of DJ-1 exhibits less binding to synaptic vesicles. These results indicate that DJ-1 associates with membranous organelles including synaptic membranes to exhibit its normal function.