Studying of pink1/parkin cellular pathway in Drosophila

描述（由申请人提供）：帕金森病是与衰老相关的第二大常见神经退行性疾病。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和PARKIN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。我们的目标是使用pink 1和parkin突变作为切入点来研究pink 1和parkin如何相互作用来调节线粒体功能，以及这种途径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，以确定pink 1/parkin通路的其他组件，研究pink 1和parkin如何相互作用的分子机制，并研究pink 1结合蛋白的作用。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包括帕金森病在内的衰老相关神经退行性疾病的发病机制提供见解，并可能发现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，是探索哺乳动物中pink 1/parkin通路成分的功能，并在神经退行性疾病特别是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。 公共卫生相关性：帕金森病是第二大常见的衰老依赖性神经退行性疾病。我们已经表明，果蝇同源的两个基因，pink 1和parkin，在一个共同的途径来调节线粒体功能的功能。该提案旨在以pink 1/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。

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.