Functional analysis of DJ-1, a causative gene for familial Parkinson's disease, and its pharmaceutical application

家族性帕金森病致病基因DJ-1的功能分析及其药物应用

• 批准号: 21390014
• 负责人: ARIGA Hiroyoshi
• 金额: $ 11.81万
• 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: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390014/
• 关键词: 脳神経疾患; 癌; ストレス; 蛋白質; 遺伝子; DJ-1; パーキンソン病; ドパミン; ミトコンドリア; 複合体I; チロシン水酸化酵素; DJ-1結合化合物; 創薬

We found that DJ-1 positively regulates synthesis and secretion of dopamine through direct interaction of DJ-1 with tyrosine hydroxylase, L-DOPA decarboxylase and VMAT-2 and through upregulation of their gene expression and that DJ-1 also positively regulates enzymatic activity of mitochondrial complex I. Furthermore, we isolated DJ-1-binding compounds that restored locomotion defect and inhibited neuronal cell death in Parkinson's disease and stroke model animals.

我们发现，DJ-1通过DJ-1与酪氨酸羟化酶，L-DOPA脱羧酶和VMAT-2的直接相互作用以及通过上调其基因表达以及DJ-1的上调，以及DJ-1还积极地调节了酶促活性的酶促活性，从而阳性地调节多巴胺的合成和分泌。线粒体复合物I。此外，我们分离了DJ-1结合化合物，这些化合物恢复了运动缺陷并抑制了帕金森氏病和中风模型动物中的神经元细胞死亡。

项目成果

Oxidative stress induction of DJ-1 protein in reactive astrocytes scavenges free radicals and reduces cell injury.

• DOI: 10.4161/oxim.2.1.7985
• 发表时间: 2009-01
• 期刊: Oxidative medicine and cellular longevity
• 作者: Yanagida T;Tsushima J;Kitamura Y;Yanagisawa D;Takata K;Shibaike T;Yamamoto A;Taniguchi T;Yasui H;Taira T;Morikawa S;Inubushi T;Tooyama I;Ariga H
• 通讯作者: Ariga H

DJ-1 associates with synaptic membranes

• DOI: 10.1016/j.nbd.2011.05.014
• 发表时间: 2011-09
• 期刊: Neurobiology of Disease
• 影响因子: 6.1
• 作者: Yukiko Usami;T. Hatano;S. Imai;S. Kubo;Shigeto Sato;S. Saiki;Y. Fujioka;Y. Ohba;Fumiaki Sato;M. Funayama;H. Eguchi;Kaori Shiba;H. Ariga;Jie Shen;N. Hattori

DJ-1 binds to mitochondrial complex I and maintains its activity

• DOI: 10.1016/j.bbrc.2009.10.025
• 发表时间: 2009-12-18
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Hayashi, Takuya;Ishimori, Chikako;Iguchi-Ariga, Sanae M. M.
• 通讯作者: Iguchi-Ariga, Sanae M. M.

大学化合物ライブラリーを用いたパーキンソン病治療薬のin siloco開発

利用大学化合物库独立开发帕金森病治疗方法

• 发表时间: 2009
• 作者: Hatakeyama S;Sugihara K;Nakayama J;Akama TO;Wong SM;Kawashima H;Zhang J;Smith DF;Ohyama C;Fukuda M;and Fukuda MN.;有賀寛芳
• 通讯作者: 有賀寛芳

Neuroprotective effect of the antiparkinsonian drug pramipexole against nigrostriatal dopaminergic degeneration in rotenone-treated mice

• DOI: 10.1016/j.neuint.2009.07.009
• 发表时间: 2009-12-01
• 期刊: NEUROCHEMISTRY INTERNATIONAL
• 影响因子: 4.2
• 作者: Inden, Masatoshi;Kitamura, Yoshihisa;Taniguchi, Takashi
• 通讯作者: Taniguchi, Takashi