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.

帕金森病是与以下疾病相关的第二常见的神经退行性疾病 老化。 PTEN 诱导激酶 1 (PINK1) 和 PARKIN 突变导致常染色体隐性遗传形式 以及一些帕金森病的散发病例。 PINK1 编码假定的丝氨酸/苏氨酸 具有线粒体靶向序列的激酶，而 PARKIN 编码假定的 E3 泛素 连接酶。果蝇含有pinkl和parkin的单一同源物，并且残基 与人类疾病相关的 PINK1 版本的突变在果蝇中很大程度上是保守的。我们 先前已经表明，果蝇中pinkl的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导致的应激敏感性。此外，pinkl 和 Parkin 在相同的遗传途径中发挥作用，pinkl 正向调节 Parkin。此外， 在pinkl突变果蝇中表达人类PINK1可以拯救pinkl突变表型，这表明 人类和果蝇pinkl在功能上是保守的。 我们将研究 Pinkl 和 Parkin 如何相互作用来调节线粒体功能。此外， 我们将进行遗传筛选，以确定 Pinkl/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。这 Pinkl/parkin 通路中新成分的鉴定可能会为以下方面提供见解： 这些疾病以及帕金森病的发病机制，并可能确定新的诊断方法 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， 旨在探索pinkl/parkin通路成分在哺乳动物中的功能并寻找潜在的 帕金森病患者这些基因的突变，以及这些基因缺陷的机制 途径可以被抑制。 加州大学洛杉矶分校为研究衰老的分子机制提供了良好的环境 相关的神经退行性疾病。如果获得资助，该 KO2 奖项将保护候选人的 将研究时间从过度延长的临床职责中解放出来，以允许进一步的研究发展。