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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：
18390253
负责人：
ARIGA Sanae
金额：
$ 11.36万
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：
2006
资助国家：
日本
起止时间：
2006 至 2007
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.(1) A role of DJ-1 in dopamine synthesis.DJ-1 was found to bind to tyrosine hydroxylase and DOPA decarboxylase and enhance their activities. Mutants found in Parkinson's disease (PD) patients lost its activities. Heterozygous mutants worked as dominant negatives towards wild-type DJ-1, suggesting that heterozygous mutants will be risk factors for onset of PD. After oxidation stresses come to cells, a cysteine residue at 106 (C106) of DJ-1 was oxidized to SOH, SO_2H and SO_3H. When C106 was weakly oxidized with SOH, and SO_2H forms, DJ-1 was activated. When C106 was strongly oxidized with the SO_3H forms, DJ-1 was inactivated. These findings suggest that DJ-1 is committed to onset of a sporadic form of PD.(2) Pharmaceutical application of DJ-1 and its binding compounds to PD.Injection of DJ-1 protein into the brain of PD model rats dramatically protected neuronal cell death and locomotive defect. Furthermore, we have identified several compounds that bind to the C106 region of DJ-1 and these compounds also protected neuronal cell death and locomotive defect in PD model rats. These compounds inhibited strong oxidation of C106 of DJ01, thereby keeping active forms of DJ-1.

DJ-1最近被证明与家族性帕金森病（PD） PARK7的发病有关。我们已经证明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PD发病的诱因。(1) DJ-1在多巴胺合成中的作用。发现DJ-1与酪氨酸羟化酶和多巴脱羧酶结合并增强其活性。在帕金森氏症（PD）患者中发现的突变体失去了其活动能力。杂合突变体对野生型DJ-1呈显性阴性，提示杂合突变体可能是PD发病的危险因素。氧化胁迫进入细胞后，DJ-1的106 （C106）半胱氨酸残基被氧化为SOH、SO_2H和SO_3H。当C106与SOH弱氧化形成SO_2H时，DJ-1被活化。当C106被SO_3H强氧化时，DJ-1失活。这些发现表明，DJ-1可能导致散发性帕金森病的发病。(2) DJ-1及其结合物在PD中的应用。PD模型大鼠脑内注射DJ-1蛋白对神经元细胞死亡和运动缺陷有明显的保护作用。此外，我们还发现了几种与DJ-1的C106区结合的化合物，这些化合物还可以保护PD模型大鼠的神经元细胞死亡和运动缺陷。这些化合物抑制了DJ01的C106的强氧化，从而保持了DJ-1的活性形式。