Endogenous Pink1 Regulates Dendritic Architecture and Spinogenesis

Abstract

Mutations in the gene for PTEN‐induced kinase 1 (PINK1) are linked to recessive Parkinson’s disease (PD) and PD with dementia (PDD). We previously discovered that overexpression of PINK1 promotes dendritic complexity through interaction with valosin containing protein (VCP) and activation of protein kinase A (PKA). Furthermore, treatment with a small molecule inhibitor of endogenous PINK1 degradation confers protection against the severe dendritic retraction elicited by 1‐methyl‐4‐phenylpyridinium (MPP+), a neurotoxin that causes parkinsonism. The objective of this study was to delineate the role of endogenous PINK1 in regulating neuronal structure and function. We hypothesized that PINK1‐deficient cortical neurons would show simplified dendritic architecture resulting in reduced synaptic input. Primary embryonic neuron cultures from Pink1‐/‐ and control mice were studied using fluorescence microscopy and electrophysiology, with ongoing studies of human PINK1‐mutated iPSC‐derived neurons. We found that loss of PINK1 expression results in diminished dendritic complexity, reduced spine density, and altered electrophysiological function. Moreover, similar changes in dendritic architecture were observed in vivo using Golgi silver‐stained mouse brain sections. We conclude that PINK1 plays a previously underappreciated role in regulating neuronal structure. Ongoing studies are aimed at understanding the signaling pathways involved, and whether these changes are developmental and/or reflect decreased resilience against neurodegenerative stressors.