Studying of pink1/parkin cellular pathway in Drosophila

描述（由申请人提供）：帕金森病是第二常见的与衰老相关的神经退行性疾病。PTEN诱导的激酶1 （PINK1）和PARKIN突变导致常染色体隐性形式和一些散发性帕金森病。PINK1编码一种假定的丝氨酸/苏氨酸激酶，具有线粒体靶向序列，而PARKIN编码一种假定的E3泛素连接酶。黑腹果蝇含有pink1和parkin的单一同源基因，与人类疾病相关的pink1和parkin基因突变的残基在果蝇中很大程度上是保守的。我们之前已经证明，由于线粒体形态和功能的缺陷，果蝇中pink1的缺失会导致雄性不育、肌肉变性和应激敏感性。此外，pink1和parkin在相同的遗传途径中起作用，pink1正调控parkin。此外，人类PINK1在PINK1突变体果蝇中的表达挽救了PINK1突变体的表型，这表明人类和果蝇的PINK1在功能上是保守的。我们旨在以pink1和parkin突变为切入点，研究pink1和parkin如何相互作用调节线粒体功能，以及该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。具体而言，我们将进行遗传筛选以鉴定pink1/parkin途径的其他组分，研究pink1和parkin相互作用的分子机制，并研究pink1结合蛋白的作用。许多老年神经退行性疾病都与线粒体功能障碍有关。pink1/parkin通路新组分的鉴定可能为了解衰老相关神经退行性疾病（包括帕金森病）的发病机制提供线索，并可能确定新的诊断工具和治疗靶点。我们的长期目标是探索哺乳动物中pink1/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，这可能需要与其他实验室合作。

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.