Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal

Kyung Min Chung, Hyunhee Park, Seonghee Jung, Shinwon Ha, Seung Jun Yoo, Hanwoong Woo, Hyang Ju Lee, Seong Who Kim, Eun Kyoung Kim, Cheil Moon, Seong Woon Yu

Research output: Contribution to journalArticle

Abstract

Programmed cell death (PCD) has significant effects on the function of neural stem cells (NSCs) during brain development and degeneration. We have previously reported that adult rat hippocampal neural stem (HCN) cells underwent autophagic cell death (ACD) rather than apoptosis following insulin withdrawal despite their intact apoptotic capabilities. Here, we report a switch in the mode of cell death in HCN cells with calpain as a critical determinant. In HCN cells, calpain 1 expression was barely detectable while calpain 2 was predominant. Inhibition of calpain in insulin-deprived HCN cells further augmented ACD. In contrast, expression of calpain 1 switched ACD to apoptosis. The proteasome inhibitor lactacystin blocked calpain 2 degradation and elevated the intracellular Ca2+ concentration. In combination, these effects potentiated calpain activity and converted the mode of cell death to apoptosis. Our results indicate that low calpain activity, due to absence of calpain 1 and degradation of calpain 2, results in a preference for ACD over apoptosis in insulin-deprived HCN cells. On the other hand, conditions leading to high calpain activity completely switch the mode of cell death to apoptosis. This is the first report on the PCD mode switching mechanism in NSCs. The dynamic change in calpain activity through the proteasome-mediated modulation of the calpain and intracellular Ca2+ levels may be the critical contributor to the demise of NSCs. Our findings provide a novel insight into the complex mechanisms interconnecting autophagy and apoptosis and their roles in the regulation of NSC death.

Original languageEnglish (US)
Pages (from-to)3052-3064
Number of pages13
JournalStem Cells
Volume33
Issue number10
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

Keywords

  • Adult neural stem cells
  • Apoptosis
  • Autophagic cell death
  • Calpain
  • Insulin withdrawal
  • Proteasome

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

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    Chung, K. M., Park, H., Jung, S., Ha, S., Yoo, S. J., Woo, H., Lee, H. J., Kim, S. W., Kim, E. K., Moon, C., & Yu, S. W. (2015). Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal. Stem Cells, 33(10), 3052-3064. https://doi.org/10.1002/stem.2082