Distinct Signaling Pathways for Autophagy-Driven Cell Death and Survival in Adult Hippocampal Neural Stem Cells

Int J Mol Sci. 2023 May 5;24(9):8289. doi: 10.3390/ijms24098289.


Autophagy is a cellular catabolic process that degrades and recycles cellular materials. Autophagy is considered to be beneficial to the cell and organism by preventing the accumulation of toxic protein aggregates, removing damaged organelles, and providing bioenergetic substrates that are necessary for survival. However, autophagy can also cause cell death depending on cellular contexts. Yet, little is known about the signaling pathways that differentially regulate the opposite outcomes of autophagy. We have previously reported that insulin withdrawal (IW) or corticosterone (CORT) induces autophagic cell death (ACD) in adult hippocampal neural stem (HCN) cells. On the other hand, metabolic stresses caused by 2-deoxy-D-glucose (2DG) and glucose-low (GL) induce autophagy without death in HCN cells. Rather, we found that 2DG-induced autophagy was cytoprotective. By comparing IW and CORT conditions with 2DG treatment, we revealed that ERK and JNK are involved with 2DG-induced protective autophagy, whereas GSK-3β regulates death-inducing autophagy. These data suggest that cell death and survival-promoting autophagy undergo differential regulation with distinct signaling pathways in HCN cells.

Keywords: ERK; GSK-3β; JNK; adult hippocampal neural stem cells; autophagic cell death; autophagy.

MeSH terms

  • Apoptosis*
  • Autophagy
  • Cell Death
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Hippocampus / metabolism
  • Insulin / metabolism
  • Insulin, Regular, Human
  • Neural Stem Cells* / metabolism
  • Signal Transduction


  • Glycogen Synthase Kinase 3 beta
  • Insulin
  • Insulin, Regular, Human