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Function of DJ-1, a causative gene for familial Parkinson's disease PARK7

家族性帕金森病致病基因 DJ-1 PARK7 的功能

基本信息

批准号：
16390248
负责人：
ARIGA Sanae
金额：
$ 8.96万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

DJ-1 has recently been shown to be responsible for onset of familial Parkinson's disease (PD), PARK7. We have shown that DJ-1 plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to trigger onset of PD. We and others have also shown that some DJ-1 is located in mitochondria in addition to the cytoplasm and nucleus and that translocation of DJ-1 to mitochondria was stimulated by oxidative stress. Furthermore, we found that DJ-1 was a positive regulator of the mitochondrial complex 1 by binding to its subunit.When a recombinant DJ-1 protein was administrated into the brain of PD model rats that had been injected to 6-hydroxydopamine (6-OHDA) in the left substantia nigra, PD phenotypes, including dopaminergic neuron death both in the substantia nigra and striatum, decrease in dopamine and dopamine transporter levels in the striatum, and motor abnormality, were dramatically improved by wild-type DJ-1 but not L166P DJ-1, a mutant form of DJ-1 found in PD patients. Furthermore, production of reactive oxygen species and cell death induced by 6-OHDA in SH-SY5Y cells were inhibited by addition of the recombinant DJ-1. We then screened low-molecular weight compounds that bind to the catalytic region of DJ-1 and found that these compounds protected SH-SY5Y cells from oxidative stress-induced cell death by inhibiting oxidation of DJ-1.These findings suggest that DJ-1 and its binding compounds are therapeutic targets for PD.

DJ-1最近已被证明是负责家族性帕金森病（PD），PARK 7的发病。我们已经表明，DJ-1在转录调控和抗氧化应激中发挥作用，其功能的丧失被认为是引发PD发作的原因。我们和其他人还表明，除了细胞质和细胞核之外，一些DJ-1还位于线粒体中，并且DJ-1向线粒体的移位受到氧化应激的刺激。此外，我们发现DJ-1是一种通过与线粒体复合物1的亚基结合的正性调节剂。当重组DJ-1蛋白被施用到PD模型大鼠的脑中时，PD表型，包括黑质和纹状体中的多巴胺能神经元死亡，纹状体中多巴胺和多巴胺转运蛋白水平的降低以及运动异常通过野生型DJ-1而不是L166 P DJ-1（在PD患者中发现的DJ-1的突变形式）得到显著改善。此外，通过添加重组DJ-1抑制了SH-SY 5 Y细胞中由6-OHDA诱导的活性氧簇的产生和细胞死亡。我们筛选了与DJ-1的催化区结合的小分子化合物，发现这些化合物通过抑制DJ-1的氧化而保护SH-SY 5 Y细胞免受氧化应激诱导的细胞死亡。这些结果表明DJ-1及其结合化合物是PD的治疗靶点。