PINK1 regulates cytoplasmic dynein and mitochondrial transport

PINK1 调节细胞质动力蛋白和线粒体运输

基本信息

批准号：
10053682
负责人：
Peter Anthony Otero
金额：
$ 4.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053682
关键词：
Adaptor Signaling Protein Affect Alzheimer&apos s Disease Autopsy Axon Biochemical Biological Assay Brain region Cell Death Cell Nucleus Cells Chronic Cytoskeleton Data Dementia Dendrites Development Disease Dynein ATPase Ensure Goals In Vitro Individual Injury Investigation Knockout Mice Lewy Body Dementia Link Measures Mediating Microscopic Microscopy Microtubules Mitochondria Molecular Monitor Movement Mutate Mutation N-terminal Nerve Degeneration Neurodegenerative Disorders Neurons PTEN gene Parkinson Disease Parkinson&apos s Dementia Parkinsonian Disorders Pathogenesis Pathogenicity Pathology Patients Phenotype Phosphorylation Phosphotransferases Play Prevalence Process Proteins Public Health Regulation Research Proposals Role Site Structure Substantia nigra structure Synapses Techniques Testing Training Vertebral column Wild Type Mouse age related neurodegeneration aging demographic dopaminergic neuron gene product in vivo insight loss of function mutant neuronal cell body novel novel therapeutic intervention pre-doctoral prevent synaptic function

项目摘要

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.

项目概要/摘要帕金森病 (PD)/帕金森病痴呆 (PDD) 是第二常见的慢性、神经退行性疾病的特征是黑质多巴胺能神经元的丧失，这种退化的致病机制通常会延伸到皮质。尽管对家族性帕金森症中突变的基因产物的分析已经表明，人们对这一现象仍然知之甚少。 PTEN 是 PD 相关基因产物之一，有助于我们了解 PD/PDD 发病机制。诱导激酶 1 (PINK1) 已被证明可以预防帕金森病损伤引起的细胞死亡。我的初步数据表明 PINK1 的保护机制仍然知之甚少。调节线粒体从体细胞到树突的出口我还发现 PINK1 可以调节。这些发现使我认识到 PINK1 会促进细胞质动力蛋白的磷酸化。通过调节动力蛋白的磷酸化，线粒体转运到树突中，我将使用先进的显微镜，生物化学和分子技术来确定新型 PINK1 是否调节磷酸化我还将研究 PD 相关 PINK1 的影响。动力蛋白磷酸化和线粒体运输的突变除了为我提供博士前课程外。培训，这项研究计划将有助于阐明 PINK1 调节线粒体的机制神经元中的分布并提供对 PD/PDD 发病机制的深入了解。