Phosphorylation of neuronal survival factor MEF2D by glycogen synthase kinase 3β in neuronal apoptosis

Abstract

Glycogen synthase kinase 3β (GSK3β) has been identified to play important roles in neuronal death. Evidence from both in vitro and in vivo studies indicates that increased GSK3β activity contributes to neurodegeneration and to the pathogenesis of Alzheimer disease. But the molecular mechanisms that underlie GSK3β-mediated neurotoxicity remain poorly understood. We reported here that myocyte enhancer factor 2D (MEF2D), a nuclear transcription factor known to promote neuronal survival, is directly phosphorylated by GSK3β. Our data showed that phosphorylation of MEF2D by GSK3β at three specific residues in its transactivation domain inhibits MEF2D transcriptional activity. Withdrawal of neuronal activity in cerebellar granule neurons activated GSK3β in the nucleus, leading to GSK3β-dependent inhibition of MEF2 function. This inhibition contributed to GSK3β-mediated neuronal toxicity. Overexpression of MEF2D mutant that is resistant to GSK3β inhibition protected cerebellar granule neurons from either GSK3β activation-or neuronal activity deprivation-induced toxicity. These results identify survival factor MEF2D as a novel downstream effector targeted by GSK3β and define a molecular link between activation of GSK3β and neuronal survival machinery which may underlie in part GSK3β-mediated neurotoxicity. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.