PINK1 regulates cytoplasmic dynein and mitochondrial transport

项目总结/摘要 帕金森病（PD）/帕金森病痴呆（PDD）是第二常见的慢性， 神经退行性疾病其特征在于黑质多巴胺能神经元的丧失， 通常伴随着病变扩展到皮层。这种变性的致病机制 仍然知之甚少，尽管对家族性帕金森病中突变的基因产物的分析， 有助于我们对PD/PDD发病机制的理解。这些PD相关基因产物之一，PTEN 诱导的激酶1（PINK 1）已显示可防止由帕金森病损伤诱导的细胞死亡。但 对这种保护的基本机制仍然知之甚少。我的初步数据显示，PINK 1 调节线粒体从索马进入树突。我还发现PINK 1调节 细胞质动力蛋白的磷酸化。这些发现使我假设PINK 1促进了 通过调节动力蛋白的磷酸化将线粒体转运到树突。我将使用先进的显微镜， 生物化学和分子技术，以确定新的PINK 1是否调节磷酸化， 动力蛋白调节其对线粒体转运的作用。我还将研究PD相关PINK 1的影响 动力蛋白磷酸化和线粒体转运的突变。除了为我提供博士预科 训练，这项研究建议将有助于阐明PINK 1调节线粒体的机制， 分布在神经元和提供洞察PD/PDD发病机制的基础。

Project Summary/Abstract Parkinson’s disease (PD)/Parkinson’s disease dementia (PDD) is the second most common chronic, neurodegenerative disorder. It is characterized by the loss of dopaminergic neurons from the substantia nigra, often with extension of pathology into the cortex. The pathogenic mechanism underlying this degeneration remains poorly understood, though analysis of gene products mutated in familial parkinsonisms has contributed to our understanding of PD/PDD pathogenesis. One of these PD-associated gene products, PTEN induced kinase 1 (PINK1), has been shown to prevent cell death induced by parkinsonian injury. However, the mechanisms underlying this protection remain poorly understood. My preliminary data indicate that PINK1 regulates mitochondrial egress from the soma into the dendrites. I have also found that PINK1 regulates phosphorylation of cytoplasmic dynein. These discoveries have led me to hypothesize that PINK1 promotes mitochondrial transport into dendrites by regulating phosphorylation of dynein. I will use advanced microscopic, biochemical, and molecular techniques to determine whether the novel PINK1 regulated phosphorylation of dynein regulates its effects on mitochondrial transport. I will also study the impact of PD-linked PINK1 mutations on dynein phosphorylation and mitochondrial transport. In addition to providing me with predoctoral training, this research proposal will help elucidate mechanisms by which PINK1 regulates mitochondrial distribution in neurons and provide insight into mechanisms underlying PD/PDD pathogenesis.