The Pink1-Parkin Pathway, Mitochondria and Parkinson's Disease

Pink1-Parkin 通路、线粒体和帕金森病

• 批准号: 8254388
• 负责人: MING GUO
• 金额: $ 14.28万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254388
• 关键词: Address; Aging; Alzheimer' s Disease; Award; Binding Proteins; Biochemical; Bypass; Clinical; Collaborations; Defect; Disease; Drosophila genus; Drosophila melanogaster; Enhancers; Environment; Event; Funding; Genes; Genetic; Genetic Screening; Goals; Homologous Gene; Human; In Vitro; Lead; Ligase; Male Sterility; Mammals; Mediating; Mitochondria; Molecular; Morphology; Mutate; Mutation; Neurodegenerative Disorders; PTEN gene; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphotransferases; Physiological; Protein-Serine-Threonine Kinases; Research; Role; Signal Pathway; Signal Transduction; System; Testing; Time; age related; base; fly; gene function; human disease; in vivo; insight; interest; mitochondrial dysfunction; muscle degeneration; muscle stress; mutant; novel diagnostics; parkin gene/protein; protein function; research and development; therapeutic target; tool; ubiquitin-protein ligase

Parkinson's disease is the second most common neurodegenerative disease associated with aging. Mutations in PTEN induced kinase 1 (PINK1) and PARKIN cause autosomal recessive forms and some sporadic cases of Parkinson's disease. PINK1encodes a putative serine/threonine kinase with a mitochondrial targeting sequence, whereas PARKIN encodes a putative E3 ubiquitin ligase. Drosophila melanogaster contains single homologs of pinkl and parkin, and the residues mutated in versions of PINK1 associated with human disease are largely conserved in flies. We have previously shown that loss of pinkl in Drosophila results in male sterility, muscle degeneration and stress sensitivity due to defects in mitochondrial morphology and function. Moreover, pinkl and parkin function in the same genetic pathway, with pinkl positively regulating parkin. In addition, expression of human PINK1 in pinkl mutant flies rescues the pinkl mutant phenotypes, suggesting that human and Drosophila pinkl are functionally conserved. We will study how Pinkl and Parkin interact to regulate mitochondrial function. In addition, we will carry out genetic screens to identify other components of the pinkl/parkin pathway. Many neurodegenerative disorders of aging are associated with mitochondrial dysfunction. The identification of new components in the pinkl/parkin pathway is likely to provide insight in pathogenesis of these diseases, as well as Parkinson's disease, and may identify new diagnostic tools and therapeutic targets. Our long-term goal, which may require collaborations with other labs, is to explore functions of pinkl/parkin pathway components in mammals and to search for potential mutations in these genes in Parkinson's disease patients, and mechanisms by which defects in this pathway can be suppressed. UCLA provides an excellent environment for research on molecular mechanisms of aging- related neurodegenerative diseases. This KO2 award, if funded, will protect the candidate's research time from overextended clinical duties to allow further research development.

帕金森病是第二大常见的神经退行性疾病， 衰老PTEN诱导的激酶1（PINK 1）和PARKIN突变导致常染色体隐性遗传形式 还有一些帕金森氏症的零星病例PINK 1编码一个推定的丝氨酸/苏氨酸 PARKIN编码一种假定的E3泛素， 连接酶黑腹果蝇含有pinkl和parkin的单一同系物， 与人类疾病相关的PINK 1突变形式在果蝇中基本上是保守的。我们 先前的研究表明，果蝇的pinkl缺失会导致雄性不育，肌肉退化， 以及由于线粒体形态和功能缺陷而引起的应激敏感性。此外，pinkl和 parkin在相同的遗传途径中起作用，pinkl正向调节parkin。此外，本发明还提供了一种方法， 人PINK 1在pink 1突变果蝇中的表达挽救了pink 1突变表型，表明 人类和果蝇的pinkl在功能上是保守的。 我们将研究Pinkl和Parkin如何相互作用以调节线粒体功能。此外，本发明还提供了一种方法， 我们将进行基因筛选，以确定pinkl/parkin途径的其他组成部分。许多 衰老的神经变性疾病与线粒体功能障碍有关。的 pinkl/parkin通路中新组分的鉴定可能提供对以下方面的了解： 这些疾病的发病机制，以及帕金森病，并可能确定新的诊断 工具和治疗目标。我们的长期目标可能需要与其他实验室合作， 目的是探索pinkl/parkin通路组分在哺乳动物中的功能， 帕金森病患者中这些基因的突变，以及这种缺陷的机制， 可以抑制通路。 加州大学洛杉矶分校为研究衰老的分子机制提供了极好的环境- 相关的神经退行性疾病。这个KO 2奖，如果资助，将保护候选人的 研究时间从过度扩展的临床职责，以允许进一步的研究发展。