Abstract

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic (DA) neurons in the substantial nigra pars compacta. Increasing evidence showed that Wnt/β-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-3β antagonists LiCl and SB216763 were used to activate Wnt/β-catenin pathway experimentally. However, the detail mechanism underlying the neuroprotection against apoptosis on DA neuron is still unclear and the interaction between Wnt/β-catenin and Nurr1 remains undisclosed. In this study, using cell biological assay we investigated the function of Wnt/β-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-3β antagonists LiCl or SB216763. The activity of Wnt/β-catenin pathway was deregulated on exposure of rotenone in a concentration-dependent manner. After the interference of β-catenin with siRNA, LiCl or SB216763 failed to protect PC12 cells from apoptosis by the rotenone toxicity. Our data confirmed that Wnt/β-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 β-catenin with Nurr1 was identified by co-immunoprecipitate analysis. In conclusion, the data suggested that Wnt/β-catenin and Nurr1 are crucial factors in the survival of DA neurons, and the activation of Wnt/β-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.

Highlights

  • Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic (DA) neurons in the substantial nigra pars compacta (SNc) [1,2]

  • In this study, using rotenone toxic cell model of PD we investigated the function of Wnt/β-catenin and Nurr1 against neurodegeneration and try to explore the mutual regulation related to their potential crosstalk in differentiated PC12 cells

  • Differentiated PC12 cells are widely used as a suitable model to explore the mechanisms of degeneration of DA neuron in Parkinson’s disease [25] and the function of the Wnt/β-catenin signaling pathway[26,27,28]

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Summary

Introduction

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic (DA) neurons in the substantial nigra pars compacta (SNc) [1,2]. Wnt and Nurr are important factors in the survival and functional maintenance of DA neurons in midbrain [5,6,7,8,9,10,11,12]. Studies have revealed that Wnt/β-catenin pathway was deregulated in cellular and animal models of toxin-induced PD [5,9,16,17] and the related genes express abnormally in DA neurons in midbrain of PD patients [18]. In this study, using rotenone toxic cell model of PD we investigated the function of Wnt/β-catenin and Nurr against neurodegeneration and try to explore the mutual regulation related to their potential crosstalk in differentiated PC12 cells

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