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

背景/假设：PTEN诱导的激酶1（PINK 1）突变，一种丝氨酸苏氨酸激酶 定位于线粒体和细胞质区室，与家族性帕金森氏病相关 疾病（PD）。PINK 1激活下游蛋白激酶A（PKA）调节线粒体 树突中的运输、内含物和融合。初步数据是通过获得资助的 parent grant认为大脑中PINK 1激活的生理后果之一是 脑源性神经营养因子（BDNF）的产生，以调节突触可塑性和存活。 虽然已知BDNF调节神经元的存活、发育和可塑性，但新出现的证据表明， 来自我们研究小组的研究表明，BDNF可以调节生物能量学和树突生长， 神经元通过增强氧化磷酸化，运输和融合突触后线粒体。 目标：这项两年期行政补充补助金的首要目标是支持 研究活动和第一年一代的关键保护研究时间，女性神经科学 博士来自不利背景的学生（斯温女士）。斯温女士收集的初步数据 目前表明，内源性切割的PINK 1（c-PINK 1）的药理学激活增强了 BDNF的产生，并且将神经元暴露于外源性重组人BDNF增加 树突中的线粒体运动并增加树突中的线粒体融合。通过提供 她的职业发展工具，在神经退行性疾病和技术技能的基本概念，女士。 Maryann Swain将测试神经元暴露于细胞外BDNF促进 线粒体向神经元（树突和突触）中高能量需求部位的运动 末端），增加线粒体的相互连接（融合），并促进能量的产生。 通过PKA介导的线粒体中关键底物的磷酸化作用，拟议 Swain女士执行的补充活动是补充性的，属于母公司的范围。 授予，因为它们与第二个目标有关（cPINK 1如何调节线粒体贩运， 目的3（c-PINK 1如何通过调节树突生长）。具体目标1：cPINK 1和 BDNF通过PINK 1和PKA调节树突中的线粒体运输/含量。具体 目的2：确定cPINK 1和BDNF如何通过以下途径增加树突中的线粒体融合： PINK 1和PKA。影响：玛丽安·斯温女士将在一个2- 一年的行政补充不仅将提高技术和概念技能，使她 在补充的第一年结束时提交一份有竞争力的NRSA博士前提案 支持，但会让她成功，并实现她成为一个独立的目标 神经退化研究者

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.