Downregulation of the Wnt/ß-catenin signaling pathway is involved in manganese-induced neurotoxicity in rat striatum and PC12 cells.
J Neurosci Res
; 92(6): 783-94, 2014 Jun.
Article
em En
| MEDLINE
| ID: mdl-24464479
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.
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MEDLINE
Assunto principal:
Corpo Estriado
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Síndromes Neurotóxicas
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Via de Sinalização Wnt
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Manganês
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Neurônios
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article