Downregulation of the Wnt/ß-catenin signaling pathway is involved in manganese-induced neurotoxicity in rat striatum and PC12 cells.

ABSTRACT

Manganese (Mn) is an essential trace element. However, exposure to excessive Mn may cause neurodegenerative disorders called manganism. Accumulating evidence indicated that dysregulation of Wnt/ß-catenin signaling was tightly associated with the onset of neurodegenerative disorders. However, whether aberrant Wnt/ß-catenin signaling contributes to Mn-induced neurotoxicity remains unknown. The present study investigates the involvement of Wnt/ß-catenin signaling in Mn-induced neurotoxicity. Western blot and immunohistochemistry analyses showed a remarkable downregulation of p-Ser9-glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin in rat striatum after Mn exposure. TUNEL assay revealed significant neuronal apoptosis following treatment with 25 mg/kg Mn. Immunofluorescent staining showed that ß-catenin was expressed predominantly in neurons, and colocalization of ß-catenin and active caspase-3 was observed after Mn exposure. Furthermore, Mn exposure resulted in PC12 cells apoptosis, which was accompanied by reduced levels of cellular ß-catenin and p-GSK-3ß. Accordingly, the mRNA level of the prosurvival factor survivin, a downstream target gene of ß-catenin, was synchronously decreased. More importantly, blockage of GSK-3ß activity with the GSK-3ß inhibitor lithium chloride could attenuate Mn-induced downregulation of ß-catenin and survivin as well as neuronal apoptosis. Overall, the present study demonstrates that downregulation of Wnt/ß-catenin signaling pathway may be of vital importance in the neuropathological process of Mn-induced neurotoxicity.