Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease

帕金森病模型中 PINK1 和 PKA 对树突稳态的调节

基本信息

批准号：
10263704
负责人：
RUBEN K DAGDA
金额：
$ 5万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263704
关键词：
A kinase anchoring protein Adaptor Signaling Protein Affect Area Binding Biochemical Biological Assay Brain Brain-Derived Neurotrophic Factor Chemical Models Chemicals Cleaved cell Cyclic AMP-Dependent Protein Kinases Cytosol Data Dendrites Disease model Etiology Exhibits Fluorescence Resonance Energy Transfer Genetic Health Homeostasis Image Impairment In Vitro Knock-out Knowledge LRRK2 gene Lead Length Link Mediating Midbrain structure Mitochondria Mitochondrial Matrix Modeling Molecular Molecular Biology Molecular Weight Mus Mutation Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Oxidative Stress PTEN gene Parkinson Disease Pathology Pharmacology Phosphorylation Phosphorylation Site Phosphotransferases Process Publishing Regulation Research Research Project Grants Role Signal Pathway Signal Transduction Substantia nigra structure Testing Therapeutic Western Blotting Work base dopaminergic neuron enhancing factor experimental study human disease imaging approach in vivo innovation motor disorder neuronal survival novel phosphoproteomics scaffold therapy development trafficking

项目摘要

PROJECT SUMMARY Mutations in PTEN-induced kinase 1 (PINK1) are associated with autosomal recessive forms of Parkinson's disease (PD). In the mitochondrion, full-length PINK1 is proteolytically processed to lower molecular weight forms which are exported to the cytosol. While full-length PINK1 has been implicated in regulating mitophagy and mitochondrial function, the understanding of the functional role(s) of endogenous cleaved PINK1 (c- PINK1) in the brain is limited. Our recent research demonstrates a link of c-PINK1 and regulation of mitochondrial trafficking and dendrite outgrowth via PKA. This model is supported by preliminary and published data from our group, showing that loss of PINK1 function in vivo and in vitro impairs PKA-mediated dendrite connectivity and mitochondrial trafficking, but the connections between these two mechanisms are unresolved. The studies proposed will fill a critical void in our understanding of how c-PINK1 regulates PKA signaling to enhance dendrite connectivity and mitochondrial trafficking in PD models. In Aim 1, the molecular mechanisms by which PINK1 and dendrite-localized PKA protect dendrites from oxidative stress will be elucidated using image-based and molecular biology approaches. Aim 2 will elucidate the mechanisms by which PINK1 and PKA regulate mitochondrial trafficking in dendrites, and specifically test the hypothesis that PINK1 acts through PKA to increase mitochondrial content by phosphorylating the mitochondrial trafficking adaptor protein Miro2. Aim 3 will determine the mechanisms by which PINK1/PKA activation modulates neurite outgrowth. This work is expected to have an impact on health and human diseases in three areas. First, characterizing the PINK1-PKA signaling pathway will identify new protective mechanisms by which this novel signaling axis maintains dendrite homeostasis. Second, experiments proposed in Aims 1 and 2 will help us understand how PINK1 activates PKA signaling in mitochondria and dendrites regulate mitochondrial trafficking and protect dendrites from oxidative stress. Third, since dysregulation of PKA signaling, mitochondrial function, neurotrophic signaling, and loss of dendrites are implicated in multiple neurodegenerative diseases, identifying new dendrite-protective mechanisms can lead to new targeted, rational therapies via enhanced protective PKA signaling.

项目概要 PTEN 诱导的激酶 1 (PINK1) 突变与帕金森病的常染色体隐性遗传形式相关疾病（PD）。在线粒体中，全长 PINK1 被蛋白水解加工成较低的分子量输出到细胞质的形式。虽然全长 PINK1 与调节线粒体自噬有关和线粒体功能，了解内源性裂解 PINK1 (c- PINK1）在大脑中的作用是有限的。我们最近的研究表明 c-PINK1 与调节的联系通过 PKA 进行线粒体运输和树突生长。该模型得到了初步和我们小组发表的数据表明，体内和体外 PINK1 功能的丧失会损害 PKA 介导的树突连接和线粒体运输，但这两种机制之间的联系是未解决。拟议的研究将填补我们对 c-PINK1 如何调节 PKA 理解的一个关键空白信号传导增强 PD 模型中的树突连接和线粒体运输。在目标 1 中，分子 PINK1 和树突局部 PKA 保护树突免受氧化应激的机制将被研究使用基于图像和分子生物学的方法进行了阐明。目标 2 将通过以下方式阐明其机制：其中 PINK1 和 PKA 调节树突中的线粒体运输，并专门检验了以下假设： PINK1 通过 PKA 发挥作用，通过磷酸化线粒体运输来增加线粒体含量接头蛋白 Miro2。目标 3 将确定 PINK1/PKA 激活调节的机制神经突生长。这项工作预计将对三个领域的健康和人类疾病产生影响。第一的，表征 PINK1-PKA 信号通路将确定新的保护机制，通过该机制，这种新型信号轴维持树突稳态。其次，目标 1 和 2 中提出的实验将帮助我们了解 PINK1 如何激活线粒体中的 PKA 信号传导以及树突如何调节线粒体运输并保护树突免受氧化应激。第三，由于 PKA 信号传导失调，线粒体功能、神经营养信号传导和树突损失与多种神经退行性疾病，识别新的树突保护机制可以带来新的有针对性的、合理的治疗方法通过增强保护性 PKA 信号传导进行治疗。