내용요약(Abstract)
Programmed cell death plays a fundamental role in human health and disease. Apoptosis-based approaches for neurodegenerative diseases often fail to yield neuroprotection, due to non-apoptotic forms of cell death and plasticity in switching between distinct cell death pathways. A fundamental gap in our understanding of molecular mechanisms of non-apoptotic cell death hinders development of novel strategies for treatment of neurodegenerative diseases.
“Autophagic cell death” is associated with the formation of autophagic vacuoles without hallmarks of apoptosis. The molecular mechanisms of autophagic cell death remain largely unknown, partly due to lack of a genuine model of autophagic cell death in mammals. The mechanism by which autophagy is interrelated with apoptosis remains one of the key unanswered questions in the field of programmed cell death. We have previously reported that adult hippocampal neural stem (HCN) cells undergo autophagic cell death (ACD) following insulin withdrawal. Autophagy is the central cell death mode of insulin-deprived HCN cells despite their intact apoptotic capabilities, representing a genuine model of ACD in mammalian cells. Here, we demonstrate an important role of calpain as a molecular switch between ACD and apoptosis. Low calpain activity, due to absence of calpain 1 and degradation of calpain 2 via the ubiquitin-proteasome system (UPS), pushes HCN cells to ACD rather than apoptosis following insulin withdrawal. On the other hand, UPS inhibition elevated the intracellular Ca2+ concetnration, which combined with blockade of calpain 2 degradation, potentiated calpain activity and subsequently suppressed ACD, converting the cell death mode to apoptosis. These data reveal a non-complementary interplay between autophagy and UPS for regulation of cell death mode in HCN cells. Our findings will help in unveiling the molecular mechanisms underlying the interconversion between apoptosis and ACD.