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J Neurosci Res. 2009 Sep;87(12):2793-802. doi: 10.1002/jnr.22098.

Overexpression of glycogen synthase kinase 3beta sensitizes neuronal cells to ethanol toxicity.

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  • 1Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Abstract

The developing central nervous system (CNS) is particularly susceptible to ethanol toxicity. The loss of neurons underlies many of the behavioral deficits observed in fetal alcohol spectrum disorders (FASD). The mechanisms of ethanol-induced neuronal loss, however, remain incompletely elucidated. We demonstrated that glycogen synthase kinase 3beta (GSK3beta), a multifunctional serine/threonine kinase, was involved in ethanol neurotoxicity. The activity of GSK3beta is negatively regulated by its phosphorylation at serine 9 (Ser9). Ethanol induced dephosphorylation of GSK3beta at Ser9 and the activation of Bax as well as caspase-3 in the developing mouse brain. These ethanol-induced alterations were ameliorated by the pretreatment of a GSK3beta inhibitor, lithium. To determine the role of GSK3beta in ethanol neurotoxicity, we overexpressed wild-type (WT), S9A mutant or dominant-negative (DN) mutant GSK3beta in a neuronal cell line (SK-N-MC). Ethanol only modestly reduced the viability of parental SK-N-MC cells but drastically induced caspase-3 activation and apoptosis in cells overexpressing WT or S9A GSK3beta, indicating that the high levels of GSK3beta or the active form of GSK3beta increased cellular sensitivity to ethanol. Contrarily, overexpression of DN GSK3beta conferred resistance to ethanol toxicity. Lithium and other specific GSK3beta inhibitors abolished the hypersensitivity to ethanol caused by WT or S9A overexpression. Bax, a proapoptotic protein, is a substrate of GSK3beta. Cells overexpressing WT or S9A GSK3beta were much more sensitive to ethanol-induced Bax activation than parental SK-N-MC cells. Our results indicate that GSK3beta may be a mediator of ethanol neurotoxicity, and its expression status in a cell may determine ethanol vulnerability.

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