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

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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.