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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.

项目总结 PTEN诱导的蛋白激酶1(PINK1)突变与常染色体隐性遗传型帕金森病相关疾病(PD)。在线粒体中，全长的PINK1被蛋白质降解处理成较低的分子量输出到细胞质中的表格。而全长PINK1与调节有丝分裂吞噬有关和线粒体功能，对内源性裂解PINK1(c-PINK1)功能作用的理解(S) 大脑中的PINK1)是有限的。我们最近的研究证明了c-PINK1与调节通过PKA进行线粒体运输和树突生长。此模型由初步的和我们小组发表的数据显示，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悬而未决。提出的研究将填补我们对c-PINK1如何调节PKA的理解的一个关键空白。在帕金森病模型中增强树突连通性和线粒体运输的信号。在目标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和分子生物学的方法来阐明。目标2将通过以下方式阐明这些机制哪些PINK1和PKA调控树突中线粒体的运输，并特别检验了这一假设 PINK1通过PKA作用，通过磷酸化线粒体运输增加线粒体含量接头蛋白Miro2。目标3将确定PINK1/PKA激活调节的机制轴突生长。这项工作预计将在三个领域对健康和人类疾病产生影响。第一, 表征PINK1-PKA信号通路将识别新的保护机制，通过这种新的信号轴维持树突的动态平衡。第二，目标1和目标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信号和树突调节线粒体运输和保护树突免受氧化应激。第三，由于PKA信号的失调，线粒体功能、神经营养信号和树突缺失与多发性硬化有关神经退行性疾病，识别新的树突保护机制可以导致新的有针对性的，理性的通过增强的保护性PKA信号进行治疗。

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）

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。