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：
10531176
负责人：
RUBEN K DAGDA
金额：
$ 5.06万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531176
关键词：
A kinase anchoring protein Adaptor Signaling Protein Affect Area Binding Biochemical Biological Assay Brain Brain-Derived Neurotrophic Factor Chemical Models Chemicals 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 PINK1 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.

项目摘要 PTEN诱导的激酶1（pink1）中的突变与帕金森氏症的常染色体隐性形式有关疾病（PD）。在线粒体中，将全长PINK1蛋白水解处理至较低的分子量出口到细胞质的形式。虽然全长pink1与调节线粒体有关和线粒体功能，对内源性裂解pink1的功能作用的理解（c- pink1）在大脑中受到限制。我们最近的研究表明了C-Pink1的联系和对线粒体贩运和树突的侵蚀通过PKA。该模型由初步和来自我们小组的数据，显示了体内PINK1功能的损失和体外损害PKA介导的树突连通性和线粒体贩运，但这两种机制之间的连接是未解决。提出的研究将填补我们对C-Pink1如何调节PKA的关键空隙信号传导以增强PD模型中的树突连通性和线粒体运输。在AIM 1中，分子 PINK1和树突定位的PKA保护树突免受氧化应激的机制将是使用基于图像的和分子生物学方法阐明。 AIM 2将通过哪个PINK1和PKA调节树突中的线粒体贩运，并特别检验了以下假设。 PINK1通过PKA起作用，通过磷酸化线粒体运输来增加线粒体含量衔接蛋白miro2。 AIM 3将确定PINK1/PKA激活调节的机制神经突生长。预计这项工作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信号通路将确定这部小说的新保护机制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如何激活线粒体和树突中的PKA信号传导来调节线粒体贩运和保护树突免受氧化应激。第三，自PKA信号的失调以来，线粒体功能，神经营养信号传导和树突的丧失与多个有关神经退行性疾病，识别新的树突形成机制可能导致新的目标，理性通过增强的保护性PKA信号传导疗法。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Editorial: Altered bioenergetics, mitochondrial quality control, and calcium signaling in the brain: Implications to age-related diseases.

DOI：
10.3389/fragi.2023.1171221
发表时间：
2023
期刊：
FRONTIERS IN AGING
影响因子：
0
作者：
Soman, Smijin K.;Martinez, Bridget;Dagda, Ruben K.
通讯作者：
Dagda, Ruben K.

Intraperitoneal Administration of Forskolin Reverses Motor Symptoms and Loss of Midbrain Dopamine Neurons in PINK1 Knockout Rats.

DOI：
10.3233/jpd-213016
发表时间：
2022
期刊：
JOURNAL OF PARKINSONS DISEASE
影响因子：
5.2
作者：
Vazquez-Mayorga, Emmanuel;Grigoruta, Mariana;Dagda, Raul;Martinez, Bridget;Dagda, Ruben K.
通讯作者：
Dagda, Ruben K.

Multiplexing Seahorse XFe24 and ImageXpress® Nano Platforms for Comprehensive Evaluation of Mitochondrial Bioenergetic Profile and Neuronal Morphology.

多重使用 Seahorse XFe24 和 ImageXpress® Nano 平台对线粒体生物能量特征和神经元形态进行综合评估。