MOLECULAR MECHANISMS OF THE PARKINSON'S DISEASE GENES

帕金森病基因的分子机制

• 批准号: 6918530
• 负责人: Asa Abeliovich
• 金额: $ 10.76万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918530
• 关键词: Parkinson' s disease; alpha synuclein; dopamine; enzyme activity; gene expression; gene interaction; gene mutation; gene targeting; genetically modified animals; human tissue; immunoprecipitation; laboratory mouse; ligase; mass spectrometry; neural degeneration; neurons; nucleic acid sequence; phenotype; posttranslational modifications; protein degradation; protein localization; protein protein interaction; protein structure; proteomics; tissue /cell culture; yeast two hybrid system; Parkinson' s disease; alpha synuclein; dopamine; enzyme activity; gene expression; gene interaction; gene mutation; gene targeting; genetically modified animals; human tissue; immunoprecipitation; laboratory mouse; ligase; mass spectrometry; neural degeneration; neurons; nucleic acid sequence; phenotype; posttranslational modifications; protein degradation; protein localization; protein protein interaction; protein structure; proteomics; tissue /cell culture; yeast two hybrid system

DESCRIPTION (provided by applicant): The investigation of familial Parkinson's disease-related syndromes is likely to provide insight into the pathogenesis of sporadic Parkinsons's disease (PD) and may suggest novel therapeutics. Mutations in the amino-terminal repeat domain of a-Synuclein (alpha-Syn) underlie rare autosomal-dominant, familial forms of PD. Familial, autosomal-recessive mutations in Parkin lead to both juvenile and adult-onset forms of PD. Furthermore, Parkin appears to possess a ubiquitin-ligase activity, implicating it in the protein degradation process. Mounting evidence implicates altered protein ubiquitination and degradation by the ubiquitin/proteasome pathway (UPP) in human neurodegenerative disorders. Both pathological and genetic data link altered protein degradation pathways with PD. A pathological hallmark of PD, the Lewy Body (LB), appears to represent intracellular inclusions composed of multiple proteins including ubiquitin, a-Synuclein (alpha-Syn), ubiquitin carboxy-terminal hydrolase (UCH-L1), and Parkin. Both Parkin and UCH-L1 are implicated in protein ubiquitination, whereas alpha-Syn appears to be a substrate of ubiquitination. The goal of this proposal is to gain an understanding of the mechanisms of action of the PD-related genes alpha-Syn, Parkin. Of particular interest are potential relationships among these molecules. I propose to combine complementary biochemical, cellular, and genetic approaches to this end.

描述（由申请人提供）：对家族性帕金森氏病相关综合症的研究很可能会提供对零星帕金森氏病（PD）发病机理的见解，并可能暗示新的治疗疗法。 A-核蛋白（α-Syn）的氨基末端重复结构域的突变是PD的稀有常染色体式，家族形式的基础。 parkin的家族性，常染色体不必要的突变导致PD的少年和成人形式。此外，帕金（Parkin）似乎具有泛素 - 连接酶活性，这与蛋白质降解过程有关。越来越多的证据表明，人类神经退行性疾病中的泛素/蛋白酶体途径（UPP）改变了蛋白质的泛素化和降解。病理和遗传数据连接都用PD改变了蛋白质降解途径。 PD的病理标志是Lewy体（LB），似乎代表了由多种蛋白质组成的细胞内夹杂物，包括多种蛋白质，包括泛素，A-核蛋白（alpha-syn），泛素羧酸氨基末端水解酶（UCH-L1）和Parkin。 Parkin和UCH-L1都与蛋白质泛素化有关，而α-Syn似乎是泛素化的底物。该提案的目的是了解与PD相关基因Alpha-Syn，Parkin的作用机理。这些分子之间的潜在关系特别令人感兴趣。我建议将互补的生化，细胞和遗传学方法结合在一起，以解决这一目标。