Endogenous PTEN-Induced Kinase 1 Regulates Dendritic Architecture and Spinogenesis

Mutations in PTEN-induced kinase 1 (PINK1) contribute to autosomal recessive Parkinson's disease with cognitive and neu-ropsychiatric comorbidities. Disturbances in dendritic and spine architecture are hallmarks of neurodegenerative and neuro-psychiatric conditions, but little is known of the impact of PINK1 on these structures. We used Pink1-/- mice to study the role of endogenous PINK1 in regulating dendritic architecture, spine density, and spine maturation. Pink1-/- cortical neu-rons of unknown sex showed decreased dendritic arborization, affecting both apical and basal arbors. Dendritic simplification in Pink1-/- neurons was primarily driven by diminished branching with smaller effects on branch lengths. Pink1-/- neu- ronsshowed 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-/- 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-/- brains. Western blot study of Pink1-/- brains of either sex revealed reduced phosphoryla-tion of NSFL1 cofactor p47, an indirect target of PINK1. Transfection of Pink1-/- neurons with a phosphomimetic p47 plas-mid 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 PINK1-mutated families.

Automated summary

Mutations in the PINK1 gene contribute to abnormal dendritic and spine structures, resulting in increased risk of cognitive and neuropsychiatric symptoms.