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

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，而与人类疾病相关的pink1基因突变的残基在果蝇中大部分是保守的。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。我们将研究Pink1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pink1/parkin通路的其他成分。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新的见解，并可能确定新的诊断工具和治疗靶点。我们的长期目标是探索哺乳动物中pink1/parkin通路成分的功能，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，这可能需要与其他实验室合作。加州大学洛杉矶分校为研究与衰老有关的神经退行性疾病的分子机制提供了良好的环境。如果获得资助，该KO2奖励将保护候选人的研究时间免受过度延长的临床职责的影响，从而允许进一步的研究发展。

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.