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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：
9891110
负责人：
RUBEN K DAGDA
金额：
$ 31.33万
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/9891110
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.

项目总结