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

Shinwon Ha, Hye Young Ryu, Kyung Min Chung, Seung Hoon Baek, Eun Kyoung Kim, Seong Woon Yu

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Neural 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. Results: We 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. Conclusion: Collectively, 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.

Original languageEnglish (US)
Article number30
JournalMolecular Brain
Volume8
Issue number1
DOIs
StatePublished - May 19 2015
Externally publishedYes

Keywords

  • Apoptosis
  • Autophagic cell death
  • Glycogen synthase kinase-3β
  • Hippocampal neural stem cells
  • Programmed cell death

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Molecular Biology

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