PINK1: Multiple mechanisms of neuroprotection.

Abstract

PTEN-induced kinase 1 (PINK1) is a serine-threonine kinase in which mutations have been identified in patients with early-onset recessive Parkinson's disease. Since its discovery, PINK1 has been heavily studied in the context of mitochondrial dysfunction and mitophagy. More recently, PINK1 has become increasingly appreciated as a signaling factor, regulating neuronal morphogenesis and titering the cellular response to stress via both autophagy-dependent and -independent mechanisms. Extensive advances have been made in understanding mitophagy regulation by PINK1 using predominantly proliferative, non-neuronal cell types, with additional functions emerging as studies shift to primary neurons and iPSC-derived neurons. Here, we review the literature supporting multiple functions of PINK1 in neuronal maturation, remodeling, and pathological states. Taken as a whole, emerging evidence indicates that PINK1 is critical for regulating dendritic morphology and preventing neurite retraction. Moreover, reduced expression of PINK1 has been observed in the absence of gene mutations in cases of sporadic dementia, broadening the scope of PINK1 a druggable target for neurodegenerative diseases beyond Parkinson's disease.