Pathogenic mechanisms of Parkinson's disease via DJ-1 and targeted drug development

DJ-1 帕金森病发病机制及靶向药物开发

• 批准号: 22300119
• 负责人: ARIGA Sanae
• 金额: $ 11.48万
• 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: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22300119/
• 关键词: 脳神経変性疾患; 癌; ストレス; 蛋白質; 遺伝子; タンパク質; 脳神経疾患

Molecular mechanisms of Parkinson’s disease pathogenesis were analyzed by functional analyses of DJ-1 protein, the product of protooncogene DJ-1, also identified as PARK7, a responsible gene for familial Parkinson’s disease. We revealed that DJ-1 transactivated key enzymes for dopamine biosynthesis, specifically bound to a dopamine transporter VMAT-2, transactivation of Nrf2-dependent anti-oxidative stress genes via specific binding and inhibition of PTEN, and was required for neurite formation in cooperation with Drebrin, an actin-binding protein. As for drug development, several low-molecular chemicals specifically bound to DJ-1 prohibited hyperoxidation of the protein and preserved a variety of physiological activities of DJ-1 under oxidative stress conditions. The chemicals were thus suggested to be promising candidates for preventive and curative drug for Parkinson’s disease.

DJ-1蛋白的功能分析，帕金森氏症的分子机制，ALS O dente park7是一个负责的家族性帕金森氏病的基因，通过特异性结合和PTEN抑制NRF2依赖性的抗氧化应激基因，并且与DREBRIN合作是神经突的形成，这是肌动蛋白结合蛋白的“氧化应激”范围。因此，建议化学物质是预防和治疗park Inson疾病的有前途的候选者。

项目成果

DJ-1 oxidized at C106 inhibits p53-activated DUSP1 expression by sequestering p53 from the promoter through binding to the DNA-binding region of p53

C106 处氧化的 DJ-1 通过与 p53 的 DNA 结合区结合将 p53 与启动子隔离来抑制 p53 激活的 DUSP1 表达

• 发表时间: 2011
• 作者: Kato;I.;Maita;H.;Takahashi-Niki;K;Iguchi-Ariga;S. M. M.;Ariga;H.
• 通讯作者: H.

分子シャペロンPrefoldinのオートファジー経路を介したタンパク質分解補助機能

分子伴侣Prefoldin通过自噬途径在蛋白水解中的辅助功能

• 发表时间: 2012
• 作者: 阿部皓;宮澤誠;田代絵梨佳;北浦廣剛;米田宏;有賀早苗;有賀寛
• 通讯作者: 有賀寛

Myc-dependent autonomous DNA replication of the sequence upstream of human c-myc gene

人类 c-myc 基因上游序列的 Myc 依赖性自主 DNA 复制

• 发表时间: 2010
• 作者: Okumura;S.;Ishikawa;S.;Niki;T.;Ariga;H.;Iguchi-Ariga;S.M.M.
• 通讯作者: S.M.M.

DJ-1の細胞外分泌による神経細胞死の抑制

DJ-1 细胞外分泌抑制神经元细胞死亡

• 发表时间: 2011
• 作者: 綿引佑実;仁木加寿子;北浦廣剛;仁木剛史;有賀早苗;有賀寛芳
• 通讯作者: 有賀寛芳

パーキンソン病原因遺伝子産物DJ-1とスパイン形成制御因子Drebrinの相互作用の解析

帕金森病致病基因产物DJ-1与脊柱形成调节因子Drebrin的相互作用分析

• 作者: Ariga;H.;近藤珠代;近藤珠代
• 通讯作者: 近藤珠代