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

家族性帕金森病致病基因 PARK7 和癌基因 DJ-1 的功能

基本信息

批准号：
18390018
负责人：
ARIGA Hiroyoshi
金额：
$ 10.96万
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：
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-l 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。我们发现DJ-1在转录调节和抗氧化应激中发挥作用，其功能的丧失被认为是触发帕金森病的发生。(1)DJ-1在多巴胺合成中的作用。DJ-1被发现与酪氨酸羟化酶和DOPA脱羧酶结合并增强它们的活性。在帕金森氏病(PD)患者中发现的突变基因失去了活性。杂合突变是野生型DJ-1的显性阴性，提示杂合突变可能是帕金森病发病的危险因素。在细胞受到氧化胁迫后，DJ-1的106位半胱氨酸残基(C106)被氧化成SOH、SO2H和SO3H。当C106被SOH弱氧化，生成SO2H时，DJ-1被激活。当C106被SO3H型强氧化时，DJ-L失活。这些发现表明DJ-1与一种散发性帕金森病的发病有关。(2)DJ-1及其与PD结合的化合物的药物应用。将DJ-1蛋白注射到PD模型大鼠的脑组织中，显著保护了神经细胞死亡和运动缺陷。此外，我们还鉴定了几种与DJ-1的C106区域结合的化合物，这些化合物也可以保护PD模型大鼠的神经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。