Feedforward activation of PRKN/parkin.

Parkinson disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain. The majority of early onset forms of Parkinson disease are a result of autosomal mutations in PRKN (parkin RBR E3 ubiquitin protein ligase) and PINK1 (PTEN induced kinase 1), which together regulate the clearance of damaged mitochondria from cells through selective autophagy of mitochondria (mitophagy). In a pair of recent papers, we characterized a secondary mechanism of activation of PRKN by PINK1 that is responsible for approximately a quarter of mitophagy in a cellular model. Our deepening understanding of PRKN-PINK1 signaling affords hope for the development of small molecule therapeutics for the treatment of Parkinson disease.