Abstract
BackgroundNeural stem cells (NSCs) hold great potential for the treatment of neurodegenerative diseases. However, programmed cell death (PCD) provoked by the harsh conditions evident in the diseased brain greatly undermines the potential of NSCs. Currently, the mechanisms of PCD that effect NSCs remain largely unknown.ResultsWe have previously reported that hippocampal neural stem (HCN) cells derived from the adult rat brain undergo autopahgic cell death (ACD) following insulin withdrawal without hallmarks of apoptosis despite their normal apoptotic capabilities. In this study, we demonstrate that glycogen synthase kinase 3β (GSK-3β) induces ACD in insulin-deprived HCN cells. Both pharmacological and genetic inactivation of GSK-3β significantly decreased ACD, while activation of GSK-3β increased autophagic flux and caused more cell death without inducing apoptosis following insulin withdrawal. In contrast, knockdown of GSK-3α barely affected ACD, lending further support to the critical role of GSK-3β.ConclusionCollectively, these data demonstrate that GSK-3β is a key regulator of ACD in HCN cells following insulin withdrawal. The absence of apoptotic indices in GSK-3β-induced cell death in insulin-deprived HCN cells corroborates the notion that HCN cell death following insulin withdrawal represents the genuine model of ACD in apoptosis-intact mammalian cells and identifies GSK-3β as a key negative effector of NSC survival downstream of insulin signaling.
Highlights
Neural stem cells (NSCs) hold great potential for the treatment of neurodegenerative diseases
We found that insulin withdrawal triggered the activation of Glycogen synthase kinase (GSK)-3β, suggesting that glycogen synthase kinase 3β (GSK-3β) may play an important role in hippocampal neural stem (HCN) cell death
GSK-3β is activated in HCN cells following insulin withdrawal In our previous reports, we demonstrated that HCN cells undergo a genuine autophagic cell death (ACD) without signs of apoptosis upon insulin withdrawal [4,6]
Summary
Neural stem cells (NSCs) hold great potential for the treatment of neurodegenerative diseases. Programmed cell death (PCD) provoked by the harsh conditions evident in the diseased brain greatly undermines the potential of NSCs. Currently, the mechanisms of PCD that effect NSCs remain largely unknown. The capability for adult neurogenesis debilitates with aging or neurodegeneration, Different types of PCD are characterized by morphological and biochemical criteria and classified into three major types: apoptosis; autophagic cell death (ACD); and necrosis. Our recent study revealed that hippocampal neural stem (HCN) cells derived from adult rats undergo ACD following insulin withdrawal [4,5,6]. HCN cells have intact apoptotic machinery; they undergo ACD with an increased autophagic flux upon insulin withdrawal. Because the degree of cell death is proportional to the level of autophagy without apoptosis activation and knockdown of the key autophagy gene Atg reduces cell death, insulin-deprived HCN cells meet the strict criteria suggested as definitive of ACD, and are considered as the most genuine model of ACD in mammalian systems [7,8]
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