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

Pink1-Parkin 通路、线粒体和帕金森病

• 批准号: 7622049
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622049
• 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; Stress; System; Testing; Time; age related; base; fly; gene function; human disease; in vivo; insight; interest; mitochondrial dysfunction; muscle degeneration; mutant; novel diagnostics; parkin gene/protein; protein function; research and development; therapeutic target; tool; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): 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. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence, whereas PARKIN encodes a putative E3 ubiquitin ligase. Drosophila melanogaster contains single homologs of pink1 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 pink1 in Drosophila results in male sterility, muscle degeneration and stress sensitivity due to defects in mitochondrial morphology and function. Moreover, pink1 and parkin function in the same genetic pathway, with pink1 positively regulating parkin. In addition, expression of human PINK1 in pink1 mutant flies rescues the pink1 mutant phenotypes, suggesting that human and Drosophila pink1 are functionally conserved. We will study how Pink1 and Parkin interact to regulate mitochondrial function. In addition, we will carry out genetic screens to identify other components of the pink1/parkin pathway. Many neurodegenerative disorders of aging are associated with mitochondrial dysfunction. The identification of new components in the pink1/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 pink1/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.

描述（由申请人提供）：帕金森病是与衰老相关的第二常见的神经退行性疾病。PTEN诱导的激酶1（PINK 1）和PARKIN的突变导致常染色体隐性遗传形式和一些帕金森病的散发病例。PINK 1编码具有线粒体靶向序列的推定的丝氨酸/苏氨酸激酶，而PARKIN编码推定的E3泛素连接酶。黑腹果蝇含有pink 1和parkin的单一同源物，并且与人类疾病相关的PINK 1版本中突变的残基在果蝇中基本上是保守的。我们以前已经表明，在果蝇中的粉红色1的损失导致雄性不育，肌肉退化和压力敏感性，由于线粒体形态和功能的缺陷。此外，pink 1和parkin在相同的遗传途径中起作用，pink 1正调控parkin。此外，人类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pink 1在功能上是保守的。我们将研究Pink 1和Parkin如何相互作用以调节线粒体功能。此外，我们还将进行基因筛选，以确定pink 1/parkin通路的其他组成部分。许多衰老的神经退行性疾病与线粒体功能障碍有关。pink 1/parkin通路中新组分的鉴定可能为这些疾病以及帕金森病的发病机制提供见解，并可能确定新的诊断工具和治疗靶点。我们的长期目标，这可能需要与其他实验室合作，是探索pink 1/parkin通路组件在哺乳动物中的功能，并在帕金森病患者中寻找这些基因的潜在突变，以及抑制该通路缺陷的机制。加州大学洛杉矶分校为研究衰老相关神经退行性疾病的分子机制提供了一个很好的环境。这个KO 2奖，如果资助，将保护候选人的研究时间从过度临床职责，以允许进一步的研究开发。