relation between ubiquitin system and parkinsonism

泛素系统与帕金森病的关系

• 批准号: 13670155
• 负责人: SUZUKI Toshiaki
• 金额: $ 2.3万
• 依托单位: The Tokyo Metropolitan Institute of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670155/
• 关键词: ubiquitin; parkinsonism; protein degradation; パーキンソン病; ユビキチンリガーゼ; プロテアソーム; パーキン; 品質管理; CHIP; 分子シャペロン; 線虫

Parkin belongs to a family of proteins with conserved UBL and RING finger motifs. Mutations in parkin cause the autosomal recessive juvenile form of parkinsonism (AR-JP). In the patients with parkin mutations, there is selective loss of dopaminergic neurons without the presence of Lewy bodies. Before this research, we showed that parkin had an ubiquitin protein-ligase activity. According to this, we began to identify the substrate and regulator of parkin. To this end, we performed yeast two-hybrid screening using parkin as a bait, purification of parkin binding proteins. Until now, we isolated some candidate of parkin substrate, and examining their reliability using C. elegans, which possesses possible parkin gene. We already isolated two allele of parkin mutant. Now we are analyzing the phenotype caused by disruption of parkin gene, although the parkin gene seems to be non-essential for the viability.

Parkin 属于具有保守 UBL 和 RING 指基序的蛋白质家族。 Parkin 突变会导致常染色体隐性青少年型帕金森病 (AR-JP)。在患有parkin突变的患者中，多巴胺能神经元选择性丧失，但不存在路易体。在这项研究之前，我们证明 Parkin 具有泛素蛋白连接酶活性。据此，我们开始鉴定parkin的底物和调节因子。为此，我们以parkin为诱饵进行酵母二杂交筛选，纯化parkin结合蛋白。到目前为止，我们分离了一些parkin底物的候选物，并利用拥有可能的parkin基因的线虫检验了它们的可靠性。我们已经分离出parkin突变体的两个等位基因。现在我们正在分析parkin基因破坏引起的表型，尽管parkin基因似乎对于生存能力不是必需的。

项目成果

鈴木俊顕, 田中啓二(分担): "Annual Review神経2002(執筆項目:ユビキチンリガーゼParkinの基礎探索研究)"中外医学社(執筆1-6). 352 (2002)

Toshiaki Suzuki、Keiji Tanaka（撰稿人）：“Annual Review Neurology 2002（撰写项目：泛素连接酶 Parkin 的基础探索性研究）”Chugai Igakusha（撰写 1-6）（2002 年）。

Mizuno Y.: "Parkin mutations (Park2)"Genetics of Movement Disorders. 305-314 (2002)

Mizuno Y.：“帕金突变（Park2）”运动障碍遗传学。

Takabe, W: "Anti-atherogenic antioxidants regulate the expression and function of proteasome a-type subunits in human endothelial cells"J. Biol. Chem.. 276. 40497-40501 (2001)

Takabe，W：“抗动脉粥样硬化抗氧化剂调节人内皮细胞中蛋白酶体 a 型亚基的表达和功能”J。

Kawakami, T.: "NEDD8 recruits E2- ubiquitin to SCF E3-ligase"EMBO J.. 20. 4003-4401 (2001)

Kawakami, T.：“NEDD8 将 E2-泛素招募到 SCF E3-连接酶”EMBO J.. 20. 4003-4401 (2001)

Kadoya K.: "Desumolyation activity of Axam, a novel Axin-binding protein, is involved in downregulation of β-catenin"Mol Cell Biol in press.

Kadoya K.：“Axam 是一种新型 Axin 结合蛋白，其解聚活性与 β-连环蛋白的下调有关”Mol Cell Biol 正在出版。