Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis.

Glycogen synthase kinase-3beta (GSK-3beta) is a critical activator of neuronal apoptosis induced by a diverse array of neurotoxic insults. However, the downstream substrates of GSK-3beta that ultimately induce neuronal death are unknown. Here, we show that GSK-3beta phosphorylates and regulates the activity of Bax, a pro-apoptotic Bcl-2 family member that stimulates the intrinsic (mitochondrial) death pathway by eliciting cytochrome c release from mitochondria.

The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons.

The cellular mechanisms underlying Purkinje neuron death in various neurodegenerative disorders of the cerebellum are poorly understood. Here we investigate an in vitro model of cerebellar neuronal death. We report that cerebellar Purkinje neurons, deprived of trophic factors, die by a form of programmed cell death distinct from the apoptotic death of neighboring granule neurons.

Inactivation of the myocyte enhancer factor-2 repressor histone deacetylase-5 by endogenous Ca(2+) //calmodulin-dependent kinase II promotes depolarization-mediated cerebellar granule neuron survival.

Cerebellar granule neuron (CGN) survival depends on activity of the myocyte enhancer factor-2 (MEF2) transcription factors. Neuronal MEF2 activity is regulated by depolarization via a mechanism that is presently unclear. Here, we show that depolarization-mediated MEF2 activity and CGN survival are compromised by overexpression of the MEF2 repressor histone deacetylase-5 (HDAC5).

A myocyte enhancer factor 2D (MEF2D) kinase activated during neuronal apoptosis is a novel target inhibited by lithium.

Depolarization promotes the survival of cerebellar granule neurons via activation of the transcription factor myocyte enhancer factor 2D (MEF2D). Removal of depolarization induces hyperphosphorylation of MEF2D on serine/threonine residues, resulting in its decreased DNA binding and susceptibility to caspases. The subsequent loss of MEF2-dependent gene transcription contributes to the apoptosis of granule neurons.

Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons.

Cerebellar granule neurons depend on insulin-like growth factor-I (IGF-I) for their survival. However, the mechanism underlying the neuroprotective effects of IGF-I is presently unclear. Here we show that IGF-I protects granule neurons by suppressing key elements of the intrinsic (mitochondrial) death pathway.

Suppression of death receptor signaling in cerebellar Purkinje neurons protects neighboring granule neurons from apoptosis via an insulin-like growth factor I-dependent mechanism.

Neuronal apoptosis contributes to the progression of neurodegenerative disease. Primary cerebellar granule neurons are an established in vitro model for investigating neuronal death. After removal of serum and depolarizing potassium, granule neurons undergo apoptosis via a mechanism that requires intrinsic (mitochondrial) death signals; however, the role of extrinsic (death receptor-mediated) signals is presently unclear.