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在转录调控和抗氧化应激中起着作用，并且认为其功能的丧失被认为会触发PD的发作。我们和其他人还表明，除了细胞质和核外，某些DJ-1位于线粒体中，并且DJ-1向线粒体的易位受到氧化应激的刺激。 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和纹状体，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，野生型DJ-1大大改善了DJ-1，但没有L166P DJ-DJ-DJ-DJ-DJ-1，这是PD患者中DJ-1的突变体形式。此外，通过添加重组DJ-1，抑制了SH-SY5Y细胞中6-OHDA诱导的活性氧和细胞死亡的产生。然后，我们筛选了与DJ-1催化区域结合的低分子量化合物，发现这些化合物通过抑制DJ-1的氧化来保护SH-SY5Y细胞免受氧化应激诱导的细胞死亡的影响。这些发现表明DJ-1及其结合化合物是Pd的治疗靶标。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease

DOI：
10.1093/brain/awh054
发表时间：
2004-02-01
期刊：
BRAIN
影响因子：
14.5
作者：
Bandopadhyay, R;Kingsbury, AE;Lees, AJ
通讯作者：
Lees, AJ

別冊・医学のあゆみ,「パーキンソン病」-最新動向

单册：医学史、“帕金森病”-最新趋势

DOI：
发表时间：
2005
期刊：
影响因子：
0
作者：
有賀寛芳;有賀早苗;平敬宏
通讯作者：
平敬宏

Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide mediated oxidation in vivo in human umbilical of vein endothelial cells.

DJ-1 的半胱氨酸-106 是人脐静脉内皮细胞体内对过氧化氢介导的氧化最敏感的半胱氨酸残基。

DOI：
发表时间：
2004
期刊：
Biochem.Biophys.Res.Commun. 317
影响因子：
0
作者：
Kinumi;T.et al.
通讯作者：
T.et al.

DJ-1 restores p53 transcription activity inhibited by Topors/p53BP3.

DOI：
10.3892/ijo.26.3.641
发表时间：
2005-03
期刊：
International journal of oncology
影响因子：
5.2
作者：
Y. Shinbo;T. Taira;Takeshi Niki;Sanae M. M. Iguchi-Ariga-Sanae-M.-M.-Iguchi-Ariga-1395935820;H. Ariga
通讯作者：
Y. Shinbo;T. Taira;Takeshi Niki;Sanae M. M. Iguchi-Ariga-Sanae-M.-M.-Iguchi-Ariga-1395935820;H. Ariga

神経変性疾患治療薬

神经退行性疾病治疗