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最近被证明是负责家族性帕金森氏病（PD），PARK7的原因。我们已经表明，DJ-1在转录调节和抗氧化应激中扮演角色，并且认为其功能的丧失被认为会触发PD的发作。（1）发现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 deparbose结合并增强其活性。在帕金森氏病（PD）患者中发现的突变体失去了活动。杂合突变体是对野生型DJ 1的主要负面因素，这表明杂合突变体将是PD发作的危险因素。氧化应力出现在细胞中后，将DJ-1的106（C106）处的半胱氨酸残基氧化为SOH，SO_2H和SO_3H。当C106用SOH弱氧化，而SO_2H形成形式时，DJ-1被激活。当C106用SO_3H形式强烈氧化时，DJ-L被灭活。这些发现表明，DJ-1致力于偶发出现PD。（2）DJ-1的药物应用及其结合化合物在PD中的结合。将DJ-1蛋白注射到PD模型大鼠的大脑中，急剧受到了神经元细胞死亡和几种化合物的结合，我们还鉴定了几个COMTOUDS，我们已经识别了COPTIS，我们已经识别了C106的COPTINE COPTINE COPTINE COPTINE COPTINE COTIND，COSTION and COTIND的COTHS INDE COPTIS and COSTIND DEC106 PD模型大鼠中的神经元细胞死亡和机车缺陷。这些化合物抑制了DJ01的C106的强氧化，从而保留了DJ-1的主动形式。