Enhancing Beta-Catenin Activity via GSK3beta Inhibition Protects PC12 Cells against Rotenone Toxicity through Nurr1 Induction

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic (DA) neurons in the substantial nigra pars compacta. Increasing evidence showed that Wnt/beta-catenin pathway and the orphan nuclear receptor Nurr1 play crucial roles in the survival and functional maintenance of DA neurons in the midbrain and GSK-3 beta antagonists LiCl and SB216763 were used to activate Wnt/beta-catenin pathway experimentally. However, the detail mechanism underlying the neuroprotection against apoptosis on DA neuron is still unclear and the interaction between Wnt/beta-catenin and Nurr1 remains undisclosed. In this study, using cell biological assay we investigated the function of Wnt/beta-catenin and its crosstalk with Nurr1 on the course of PC12 cell degeneration in vitro. Our data showed that PC12 cell viability was inhibited by rotenone, but attenuated by GSK-3 beta antagonists LiCl or SB216763. The activity of Wnt/beta-catenin pathway was deregulated on exposure of rotenone in a concentration-dependent manner. After the interference of beta-catenin with siRNA, LiCl or SB216763 failed to protect PC12 cells from apoptosis by the rotenone toxicity. Our data confirmed that Wnt/beta-catenin signaling activated by LiCl or SB216763 enhanced Nurr1 expression to 2.75 +/- 0.55 and 4.06 +/- 0.41 folds respectively compared with control detected by real-time PCR and the interaction of beta-catenin with Nurr1 was identified by co-immunoprecipitate analysis. In conclusion, the data suggested that Wnt/beta-catenin and Nurr1 are crucial factors in the survival of DA neurons, and the activation of Wnt/beta-catenin pathway exerts protective effects on DA neurons partly by mean of a co-active pattern with Nurr1. This finding may shed a light on the potential treatment of Parkinson disease.