PICK1 inhibits the E3 ubiquitin ligase activity of Parkin and reduces its neuronal protective effect

Significance Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by progressive deterioration of motor function caused by loss of dopamine-producing neurons. Currently, there is no treatment that could stop the progress of the disease. Loss-of-function mutations in Parkin account for ∼50% of early onset PD. Parkin functions as an E3 ubiquitin ligase that exhibits multiple protective roles especially in dopaminergic neurons. Here, we demonstrate that PICK1 directly binds to Parkin. PICK1 is a potent endogenous inhibitor of Parkin’s E3 ubiquitin ligase activity and blocks Parkin’s protective functions. Conversely, knockout of PICK1 enhances the neuroprotective effect of Parkin. Thus, the reduction of PICK1 may provide a therapeutic target for the treatment of PD.