Studying of pink1/parkin cellular pathway in Drosophila

果蝇pink1/parkin细胞通路的研究

• 批准号: 7848860
• 负责人: MING GUO
• 金额: $ 30.88万
• 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: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848860
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Binding Proteins; Biochemical; Bypass; Collaborations; Defect; Disease; Drosophila genus; Drosophila melanogaster; Enhancers; Event; 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; Process; Protein-Serine-Threonine Kinases; Role; Signal Pathway; Signal Transduction; Stress; System; Testing; age related; base; fly; gene function; human disease; in vivo; insight; interest; mitochondrial dysfunction; muscle degeneration; mutant; novel diagnostics; parkin gene/protein; protein function; public health relevance; 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 and PARKIN 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 aim to use pink1 and parkin mutations as an entry point to study how pink1 and parkin interact to regulate mitochondrial function, and how dysregulation of this pathway leads to compromised mitochondrial function, which is important in Parkinson's disease pathogenesis. Specifically, we will carry out genetic screens to identify other components of the pink1/parkin pathway, investigate the molecular mechanisms of how pink1 and parkin interact and study the role of a pink1-binding protein. Many neurodegenerative disorders of aging are associated with mitochondrial dysfunction. The identification of new components in pink1/parkin pathway is likely to provide insight in pathogenesis of aging-related neurodegenerative diseases, including 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 patients with neurodegenerative diseases particularly Parkinson's disease, and mechanisms by which defects in this pathway can be suppressed. PUBLIC HEALTH RELEVANCE: Parkinson's disease is the second most common aging-dependent neurodegenerative diseases. We have shown that Drosophila homologs of two genes, pink1 and parkin, function in a common pathway to regulate mitochondrial function. The proposal aims to use pink1/parkin as an entry point to study the role of mitochondrial function in regulating age-dependent processes.

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 诱导激酶 1 (PINK1) 和 PARKIN 突变会导致常染色体隐性遗传形式和一些散发性帕金森病病例。 PINK1 编码具有线粒体靶向序列的推定丝氨酸/苏氨酸激酶，而 PARKIN 编码推定 E3 泛素连接酶。果蝇含有pink1和parkin的单一同源物，与人类疾病相关的PINK1和PARKIN版本中突变的残基在果蝇中很大程度上是保守的。我们之前已经表明，果蝇中pink1的缺失会因线粒体形态和功能缺陷而导致雄性不育、肌肉退化和应激敏感性。此外，pink1和parkin在相同的遗传途径中发挥作用，其中pink1正向调节parkin。此外，人类PINK1在pink1突变果蝇中的表达挽救了pink1突变表型，表明人类和果蝇pink1在功能上是保守的。我们的目标是以pink1和parkin突变为切入点，研究pink1和parkin如何相互作用来调节线粒体功能，以及该通路的失调如何导致线粒体功能受损，这在帕金森病的发病机制中很重要。具体来说，我们将进行遗传筛选来鉴定pink1/parkin通路的其他成分，研究pink1和parkin如何相互作用的分子机制，并研究pink1结合蛋白的作用。许多衰老神经退行性疾病与线粒体功能障碍有关。 Pink1/parkin 通路中新成分的鉴定可能有助于深入了解与衰老相关的神经退行性疾病（包括帕金森病）的发病机制，并可能确定新的诊断工具和治疗靶点。我们的长期目标（可能需要与其他实验室合作）是探索哺乳动物中pink1/parkin通路成分的功能，并寻找神经退行性疾病（特别是帕金森病）患者中这些基因的潜在突变，以及缺陷的机制。该途径可以被抑制。 公共健康相关性：帕金森病是第二常见的衰老依赖性神经退行性疾病。我们已经证明，果蝇的两个基因（pink1 和 Parkin）的同源物在调节线粒体功能的共同途径中发挥作用。该提案旨在以pink1/parkin为切入点，研究线粒体功能在调节年龄依赖性过程中的作用。