Mutations in PTEN-induced kinase 1 (PINK1) contribute to autosomal recessive Parkinson's disease with cognitive and neuropsychiatric comorbidities. Disturbances in dendritic and spine architecture are hallmarks of neurodegenerative and neuropsychiatric conditions, but little is known of the impact of PINK1 on these structures. We used Pink1 2/2 mice to study the role of endogenous PINK1 in regulating dendritic architecture, spine density, and spine maturation. Pink1 2/2 cortical neurons of unknown sex showed decreased dendritic arborization, affecting both apical and basal arbors. Dendritic simplification in Pink1 2/2 neurons was primarily driven by diminished branching with smaller effects on branch lengths. Pink1 2/2 neurons showed reduced spine density with a shift in morphology to favor filopodia at the expense of mushroom spines. Electrophysiology revealed significant reductions in miniature EPSC (mEPSC) frequency in Pink1 2/2 neurons, consistent with the observation of decreased spine numbers. Transfecting with human PINK1 rescued changes in dendritic architecture, in thin, stubby, and mushroom spine densities, and in mEPSC frequency. Diminished spine density was also observed in Golgi-Cox stained adult male Pink1 2/2 brains. Western blot study of Pink1 2/2 brains of either sex revealed reduced phosphorylation of NSFL1 cofactor p47, an indirect target of PINK1. Transfection of Pink1 2/2 neurons with a phosphomimetic p47 plasmid rescued dendritic branching and thin/stubby spine density with a partial rescue of mushroom spines, implicating a role for PINK1-regulated p47 phosphorylation in dendrite and spine development. These findings suggest that PINK1-dependent synaptodendritic alterations may contribute to the risk of cognitive and/or neuropsychiatric pathologies observed in PINK1mutated families.
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.
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