Phosphorylation of Neuronal Survival Factor MEF2D by Glycogen Synthase Kinase 3β in Neuronal Apoptosis

Glycogen synthase kinase 3 beta (GSK3 beta) has been identified to play important roles in neuronal death. Evidence from both in vitro and in vivo studies indicates that increased GSK3 beta activity contributes to neurodegeneration and to the pathogenesis of Alzheimer disease. But the molecular mechanisms that underlie GSK3 beta-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 GSK3 beta. Our data showed that phosphorylation of MEF2D by GSK3 beta at three specific residues in its transactivation domain inhibits MEF2D transcriptional activity. Withdrawal of neuronal activity in cerebellar granule neurons activated GSK3 beta in the nucleus, leading to GSK3 beta-dependent inhibition of MEF2 function. This inhibition contributed to GSK3 beta-mediated neuronal toxicity. Overexpression of MEF2D mutant that is resistant to GSK3 beta inhibition protected cerebellar granule neurons from either GSK3 beta activation-or neuronal activity deprivation-induced toxicity. These results identify survival factor MEF2D as a novel downstream effector targeted by GSK3 beta and define a molecular link between activation of GSK3 beta and neuronal survival machinery which may underlie in part GSK3 beta-mediated neurotoxicity.