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

Mol Brain 2015 May 19;8:30. Epub 2015 May 19.

Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 711-873, Republic of Korea.

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.

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http://dx.doi.org/10.1186/s13041-015-0119-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4436742PMC
May 2015
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References

(Supplied by CrossRef)

DK Ma et al.
Cell Res 2009

FH Gage et al.
Science 2000

L Sommer et al.
Prog Neurobiol 2002

SH Baek et al.
Autophagy 2009

KM Chung et al.
BMB Rep 2013

SW Yu et al.
Stem Cells 2008

HM Shen et al.
Autophagy 2011

D Denton et al.
Cell Death Differ 2012

T Shintani et al.
Science 2004

G Kroemer et al.
Mol Cell 2010

D Gozuacik et al.
Curr Top Dev Biol 2007

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