Dendrite regulation by the mitochondrial kinase PINK1: Implications for PD/LBD

Dendrite regulation by the mitochondrial kinase PINK1: Implications for PD/LBD PROJECT SUMMARY. Synaptic loss is a major structural correlate of dementia, and reduced spine density is observed in Alzheimer’s disease (AD) and the Lewy body dementia (LBD) disease spectrum. Autosomal recessive mutations in PTEN-induced kinase 1 (PINK1) cause early-onset Parkinson’s disease (PD) and PD with dementia (PDD), with heterozygous carriers exhibiting cognitive-executive dysfunction and cortical degeneration in the absence of motor symptoms. Given that wild type PINK1 is reduced in the cortex of patients with sporadic PDD and AD, we studied the role of endogenous PINK1 in regulating dendritic branching, spine density and function in the previous project period. We elucidated a novel signaling pathway by which PINK1 promotes dendritic arborization, discovered that Pink1-/- neurons exhibit reduced dendritic spine density in vitro and in vivo, and identified a novel PINK1-regulated motor protein phosphorylation site. In the current proposal, we will test the hypothesis that alterations in dendritic mitochondrial transport in PINK1-deficient neurons result in defective mitochondrial support of synaptic plasticity. We will employ molecular genetic manipulations, glutamate uncaging and electrophysiology to study the impact of PINK1 loss-of-function on dendritic transport of mitochondria, mitochondrial motor proteins, and perisynaptic mitochondrial positioning in Pink1-/- mouse neurons and PINK1-mutated patient iPSC-derived cortical neurons. We will also study the impact of PINK1 deficiency on spine dynamics and cognitive function in Pink1-/- mice in vivo. A better understanding of novel PINK1- driven mechanisms that promote dendritic health and spine function may yield valuable insights relevant to neuroprotection for these devastating neurodegenerative diseases.