Diverse Functions of Parkin in Midbrain Dopaminergic Neurons

Abstract Parkinson's disease (PD) is characterized by preferential degeneration of midbrain dopaminergic neurons that contributes to its typical clinical manifestation. Mutations in the parkin gene ( PARK2 ) represent a relatively common genetic cause of early onset PD. Parkin has been implicated in PINK1‐dependent mitochondrial quantity control by targeting dysfunctional mitochondria to lysosomes via mitophagy. Recent evidence suggests that parkin can be activated in PINK1‐independent manner to regulate synaptic function in human dopaminergic neurons. Neuronal activity triggers CaMKII‐mediated activation of parkin and its recruitment to synaptic vesicles where parkin promotes binding of synaptojanin‐1 to endophilin A1 and facilitates vesicle endocytosis. In PD patient neurons, disruption of this pathway on loss of parkin leads to defective recycling of synaptic vesicles and accumulation of toxic oxidized dopamine that at least in part explains preferential vulnerability of midbrain dopaminergic neurons. These findings suggest a convergent mechanism for PD‐linked mutations in parkin, synaptojanin‐1, and endophilin A1 and highlight synaptic dysfunction as an early pathogenic event in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.