Parkin-Dependent Degradation of the F-Box Protein Fbw7β Promotes Neuronal Survival in Response to Oxidative Stress by Stabilizing Mcl-1

Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons resulting in motor dysfunction. While most PD is sporadic in nature, a significant subset can be linked to either dominant or recessive germ line mutations. PARK2, encoding the ubiquitin ligase parkin, is the most frequently mutated gene in hereditary Parkinson's disease. Here, we present evidence for a neuronal ubiquitin ligase cascade involving parkin and the multisubunit ubiquitin ligase SCFFbw7 beta. Specifically, parkin targets the SCF substrate adapter Fbw7 beta for proteasomal degradation. Furthermore, we show that the physiological role of parkin-mediated regulation of Fbw7 beta levels is the stabilization of the mitochondrial prosurvival factor Mcl-1, an SCFFbw7 beta target in neurons. We show that neurons depleted of parkin become acutely sensitive to oxidative stress due to an inability to maintain adequate levels of Mcl-1. Therefore, loss of parkin function through biallelic mutation of PARK2 may lead to death of dopaminergic neurons through unregulated SCFFbw7 beta-mediated ubiquitylation-dependent proteolysis of Mcl-1.