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

• 批准号: 10351838
• 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
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351838
• 关键词: A kinase anchoring protein; Academia; Adaptor Signaling Protein; Address; Administrative Supplement; Adolescent; Award; Bioenergetics; Biological Assay; Biology; Brain; Brain-Derived Neurotrophic Factor; Cleaved cell; Complement; Cyclic AMP-Dependent Protein Kinases; Cytosol; Data; Dendrites; Development; Disadvantaged; Disease; Disease model; Doctor of Philosophy; Dynamin; Female; Foundations; Funding; Generations; Goals; Grant; Health; Homeostasis; Human; Imaging Techniques; Immunofluorescence Immunologic; Kinetins; Knowledge; Length; Maintenance; Mediating; Mentors; Midbrain structure; Mitochondria; Modeling; Molecular; Morphology; Movement; Mutate; Mutation; National Research Service Awards; Nerve Degeneration; Nerve Growth Factors; Neurons; Neurosciences; Neurotrophic Tyrosine Kinase Receptor Type 2; Oxidative Phosphorylation; Oxidative Stress; PTEN gene; Parents; Parkinson Disease; Peptide Hydrolases; Pharmacology; Phosphorylation; Phosphotransferases; Physiological; Presynaptic Terminals; Production; Protein Kinase; Protein Kinase A Inhibitor; Protein-Serine-Threonine Kinases; Proteins; Recombinants; Regulation; Research; Research Activity; Research Personnel; Research Project Grants; Research Support; Resistance; Respiration; Scaffolding Protein; Signal Transduction; Site; Soman; Specificity; Substantia nigra structure; Synaptic plasticity; Talents; Technical Expertise; Techniques; Testing; Time; Training; United States National Institutes of Health; Work; base; career development; cinematography; disadvantaged background; doctoral student; dopaminergic neuron; expectation; extracellular; graduate student; innovation; mitochondrial dysfunction; mutant; neuronal survival; neuroprotection; parent grant; post-doctoral training; postsynaptic; pre-doctoral; protein kinase inhibitor; skills; time use; tool development; trafficking; tripolyphosphate

Background/Premise: Mutations in PTEN-induced Kinase 1 (PINK1), a serine threonine kinase localized to mitochondrial and cytosolic compartments, is associated with familial forms of Parkinon’s Disease (PD). PINK1 activates downstream Protein Kinase A (PKA) to regulate mitochondrial trafficking, content and fusion in dendrites. Preliminary data garnered via the support of the funded parent grant suggest that one of the physiological consequences of PINK1 activation in the brain is the production of brain-derived neurotrophic factor (BDNF) to modulate synaptic plasticity and survival. While it is known that BDNFs regulate neuronal survival, development and plasticity, emerging evidence from our research group suggests that BDNF can modulate the bioenergetics and dendrite outgrowth of neurons by enhancing oxidative phosphorylation, trafficking and fusion of postsynaptic mitochondria. Objective: For this two-year administrative supplement grant, the overarching goal is to support the research activities and critical protected research time of a first-year generation, female Neuroscience Ph.D. student (Ms. Swain) from a disadvantage background. Preliminary data garnered by Ms. Swain currently show that pharmacological activation of endogenous cleaved PINK1 (c-PINK1) enhances the production of BDNF, and that exposing neurons to exogenous recombinant human BDNF increases mitochondrial movement in dendrites and increases mitochondrial fusion in dendrites. By providing her the career development tools, foundational concepts in neurodegeneration and technical skills, Ms. Maryann Swain will test the hypothesis that the exposure of neurons to extracellular BDNF promotes the movement of mitochondria to sites of high energy demand in neurons (dendrites and synaptic terminals), increases mitochondrial interconnectivity (fusion), and boosts energy production in the brain via PKA-mediated phosphorylation of key substrates in mitochondria. The proposed supplemental activities performed by Ms. Swain are complementary and within the scope of the parent grant as they relate to the second aim (how cPINK1 regulates mitochondrial trafficking in dendrites)aim 3 (how c-PINK1 regulates dendrite outgrowth via ). Specific Aim 1: how cPINK1 and BDNF regulates mitochondrial trafficking/content in dendrites through PINK1 and PKA. Specific Aim 2: Determine how cPINK1 and BDNF increases mitochondrial fusion in dendrites through PINK1 and PKA. Impact: The training that Ms. Maryann Swain will receive under the support of a 2- year administrative supplement will not only enhance the technical and conceptual skills to enable her to submit a competitive NRSA predoctoral proposal by the end of the first year of supplemental support, but will allow her to be successful and attain her goal of becoming an independent neurodegeneration researcher in academia.

背景/前提：PTEN 诱导的激酶 1 (PINK1)（一种丝氨酸苏氨酸激酶）的突变 定位于线粒体和细胞质区室，与帕金森病的家族形式相关 疾病 (PD)。PINK1 激活下游蛋白激酶 A (PKA) 来调节线粒体。 通过资助的支持收集的树突中的贩运、内容和融合的初步数据。 家长资助表明，大脑中 PINK1 激活的生理后果之一是 产生脑源性神经营养因子（BDNF）来调节突触可塑性和存活。 虽然众所周知 BDNF 调节神经元的存活、发育和可塑性，但新的证据表明 我们的研究小组表明 BDNF 可以调节生物能学和树突生长 通过增强突触后线粒体的氧化磷酸化、运输和融合来影响神经元。 目标：对于这项为期两年的行政补充补助金，总体目标是支持 第一年女性神经科学的研究活动和关键受保护研究时间 来自弱势背景的博士生（Swain 女士） Swain 女士收集的初步数据。 目前表明，内源性裂解 PINK1 (c-PINK1) 的药理激活可增强 BDNF 的产生，并且将神经元暴露于外源重组人 BDNF 会增加 通过提供树突中的线粒体运动并增加树突中的线粒体融合。 她介绍了职业发展工具、神经退行性变的基本概念和技术技能， Maryann Swain 将检验以下假设：神经元暴露于细胞外 BDNF 会促进 线粒体向神经元（树突和突触）高能量需求部位的运动 终端），增加线粒体互连性（融合），并提高线粒体的能量产生 大脑通过 PKA 介导的线粒体关键底物磷酸化。 Swain 女士进行的补充活动是补充性的，并且在家长的范围内 授予，因为它们与第二个目标相关（cPINK1如何调节线粒体运输） 树突）目标 3（c-PINK1 如何通过 调节树突生长）。 BDNF 通过 PINK1 和 PKA Specific 调节树突中的线粒体运输/含量。 目标 2：确定 cPINK1 和 BDNF 如何通过以下方式增加树突中的线粒体融合： PINK1 和 PKA。影响：Maryann Swain 女士将在 2- 的支持下接受培训。 年行政补充不仅会增强技术和概念技能，使她 在补充课程第一年结束之前提交一份有竞争力的 NRSA 博士前提案 支持，但将使她成功并实现成为独立人士的目标 学术界的神经退行性疾病研究人员。