CDK5-mediated phosphorylation and autophagy of RKIP regulate neuronal death in Parkinson's disease

Raf kinase inhibitor protein (RKIP) is a major negative mediator of the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. The downregulation of RKIP is correlated with many cancers, but the mechanisms that underlie this downregulation and its roles in the nervous system remain unclear. Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif “KLYEQ” in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA). Furthermore, in the brain sample of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride-induced and transgenic PD models, we demonstrate that CDK5-mediated phosphorylation and autophagy of RKIP are involved in the overactivation of the ERK/MAPK cascade, leading to S-phase reentry and neuronal loss. These findings provide evidence for the role of the CDK5/RKIP/ERK pathway in PD pathogenesis and suggest that this pathway may be a suitable therapeutic target in PD.