Overexpression of DJ-1 protects against C2-ceramide-induced neuronal death through activation of the PI3K/AKT pathway and inhibition of autophagy.

ABSTRACT

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder. It is characterized by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Early-onset familial forms of PD are associated with mutations in several genes, including parkin, pink1 and dj-1. DJ-1 encodes a protein whose neuroprotective function has not been completely clarified yet. We aim to understand the neuroprotective mechanisms of DJ-1, in particular, DJ-1's involvement in the regulation of the PI3K/PTEN/AKT/mTOR pathway and neuronal autophagy in a neurotoxic context induced by C2-ceramide, by using CAD cells, a murine cathecolaminergic cell line. We demonstrated that C2-ceramide induces CAD cell death associated with decreased phosphorylation of PTEN at Ser380, AKT at Ser473, and mTOR at Ser2448; and increased of autophagic flux (increased LC3-II and autophagosome formation). Additionally, we showed that overexpression of DJ-1 protects against C2-ceramide-induced neuronal death and it is not associated with change in the phosphorylation of mTOR at Ser2448. In conclusion, these data suggest that DJ-1 reinforces the PI3K/AKT survival pathway and inhibits autophagy, probably by a mechanism independent from mTOR.