Regulation of autophagic cell death by glycogen synthase kinase-3β in adult hippocampal neural stem cells following insulin withdrawal

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.

E93 Integrates Neuroblast Intrinsic State with Developmental Time to Terminate MB Neurogenesis via Autophagy

“…This is consistent with NSCs being eliminated by terminal differentiation; however, some could also undergo apoptosis or autophagy and significant caspase-dependent cell death is observed in regions where NSCs normally reside [60][61][62]. It has also been reported that cultured hippocampal NSCs undergo autophagy and then death when insulin is withdrawn and that NSC loss can be reduced when Atg7 is knocked down [63,64]. Imp, Syp, and E93 are all evolutionarily conserved, suggesting that the mechanism regulating neurogenesis termination could also be conserved.…”

Autophagy-dependent cell death – where, how and why a cell eats itself to death

“…literature survey shows that autophagy is a physiologically relevant mechanism for cell killing, and has inspired further investigation into the subcellular characteristics of the process and its underlying mechanisms. In particular, two validated models of ADCD, insulin withdrawal in adult hippocampal neural (HCN) stem cells (Ha et al, 2015;Yu et al, 2008) and resveratrol (RSV) treatment of the lung cancer cell line A549 (Dasari et al, 2017a), have been used to dissect the molecular regulation of ADCD. Both models fulfill the strict criteria of ADCD, as cell death depends on several autophagic genes and does not involve other cell death modalities.…”

“…Therefore, the function of Ral and exocyst in autophagic cell death may be specific to the fly. ADCD that is induced by insulin deprivation in HCN cells involves the activation of glycogen synthase kinase-3β (GSK-3β) downstream of insulin receptor signaling (Ha et al, 2015), and also requires release of Ca 2+ from ER stores, as a result of increases in expression of the Ryr3 ryanodine receptor . However, it is not known how either an increase in cellular Ca 2+ or active GSK-3β links to lethal autophagy.…”

Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits

“…In mammals, authentic cases of ACD are rare. We have previously reported that adult hippocampal neural stem (HCN) cells isolated from adult rats undergo ACD following insulin withdrawal despite their intact apoptotic capabilities [5][6][7][8]. Autophagy flux is increased in insulin-deprived HCN cells without signs of apoptosis or necrosis, and genetic inactivation of autophagy protects HCN cells from cell death induced by insulin withdrawal.…”