PINK1 regulates cytoplasmic dynein and mitochondrial transport

项目摘要/摘要 帕金森氏病(PD)/帕金森氏病痴呆症(PDD)是第二常见的慢性疾病， 神经退行性疾病。它的特点是黑质多巴胺能神经元的丢失， 通常伴随着病理向皮质的延伸。这种退变的致病机制 仍然知之甚少，尽管对家族性帕金森综合征基因产物突变的分析已经 有助于我们对PD/PDD发病机制的理解。其中一种与帕金森病相关的基因产物是PTEN 诱导激酶1(PINK1)，已被证明可以防止帕金森氏症损伤引起的细胞死亡。然而， 这种保护背后的机制仍然知之甚少。我的初步数据显示PINK1 调节线粒体从胞体到树突的出口。我还发现PINK1调节 胞质动力蛋白的磷酸化。这些发现让我假设PINK1促进了 线粒体通过调节动力蛋白的磷酸化进入树突。我将使用先进的显微镜， 生化和分子技术来确定新的PINK1是否调节 动力蛋白调节其对线粒体运输的影响。我还将研究与PD相关的PINK1的影响 动力蛋白磷酸化和线粒体转运的突变。除了为我提供博士前研究 训练，这项研究建议将有助于阐明PINK1调节线粒体的机制 并提供了对PD/PDD发病机制的洞察。

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.