Therapeutic Potential of Small Molecule Activators of the PINK1-Parkin Pathway

描述（由申请人提供）：线粒体DNA突变导致许多严重的儿童期线粒体综合征，线粒体功能障碍与常见的年龄相关疾病（如糖尿病、阿尔茨海默病和帕金森病）相关。然而，目前还没有治愈这些疾病的方法。治疗线粒体疾病的一个很有前途的途径是使用化学制剂来激活细胞质量控制途径，这种途径能够选择性地消除功能失调的线粒体。最近的研究表明，pten诱导的激酶1 （PINK1）和E3泛素连接酶Parkin在这一途径中起作用。此外，我们的初步研究表明，PINK1和Parkin在果蝇黑腹果蝇中的过表达可以拯救线粒体疾病的果蝇模型，从而验证了该途径的治疗潜力。我们的目标是测试PINK1-Parkin通路激活化合物是否也可以拯救线粒体疾病的果蝇模型。为实现这一目标，我们提出两个目标。首先，我们提出测试PINK1-Parkin通路激活化合物是否可以挽救与我们的果蝇线粒体疾病模型相关的易于测定的表型。其次，我们将测试在我们的第一个目标中确定的最有希望的化合物是否以PINK1和帕金森依赖的方式起作用，以及这些化合物是否可以拯救我们的线粒体疾病模型的其他表型。我们的工作将有可能发现可用于治疗多种人类疾病的化合物。

DESCRIPTION (provided by applicant): Mitochondrial DNA mutations cause a number of severe childhood-onset mitochondrial syndromes, and mitochondrial dysfunction is associated with common age-related diseases such as diabetes, Alzheimer's disease and Parkinson's disease. However, there are currently no curative treatments for any of these diseases. One promising avenue of therapy for mitochondrial diseases involves the use of chemical agents that can activate a cellular quality control pathway that is capable of selectively eliminating dysfunctional mitochondria. Recent work indicates that the PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin function in such a pathway. Moreover, our preliminary studies demonstrate that overexpression of PINK1 and Parkin in the fruit fly Drosophila melanogaster rescues fly models of mitochondrial disease, thus validating the therapeutic potential of this pathway. The goal of our proposal is to test whether PINK1-Parkin pathway activating compounds identified from high-throughput cell culture-based screens can also rescue fly models of mitochondrial disease. To achieve this goal, we propose two aims. First, we propose to test whether PINK1-Parkin pathway activating compounds identified from cell culture-based screens can rescue an easily assayed phenotype associated with our Drosophila models of mitochondrial disease. Second, we will test whether the most promising compounds identified in our first aim act in a PINK1 and Parkin-dependent fashion, and whether these compounds can rescue other phenotypes of our mitochondrial disease models. Our work will potentially identify compounds that can be used to treat a wide variety of human diseases.