Valosin-Containing Protein (VCP)/p97 is a key mediator between autopahgic cell death and apoptosis in adult hippocampal neural stem cells followin insulin withdrawal

Abstract

Programmed cell death (PCD) plays essential roles in regulation of survival and function of neural stem cells (NSCs). Abnormal regulation of this process is associated with aging and neurodegenerative diseases. However, the mechanisms underlying the PCD of NSCs remain largely unknown. Therefore, understanding the mechanism of PCD in NSCs is crucial for exploring therapeutic strategy for the treatment of neurodegenerative diseases. We have previously reported that adult rat hippocampal neural stem (HCN) cells undergo autophagic cell death (ACD) following insulin withdrawal without apoptotic signs despite their normal apoptotic capabilities. It is unknown how interconnection between ACD and apoptosis is mediated in insulin-deprived HCN cells. Valosin-containing protein (VCP)/p97 is known to be essential for autophagosome maturation in mammalian cells. In this study, we report that VCP regulates the rate of autophagic flux in HCN cells following insulin withdrawal, suggesting the novel roles of VCP at other steps of autophagy as well as maturation. Particularly, VCP is expressed abundantly in HCN cells compared to hippocampal tissue and neurons. Pharmacological and genetic inhibition of VCP significantly decreased ACD and autophagy markers, while apoptotic cell death was induced in insulin-depleted HCN cells. Taken together, these data demonstrate that VCP may play an essential role in completion of ACD and mediation of crosstalk between ACD and apoptosis in HCN cells following insulin withdrawal. Elucidating the mechanism by which VCP regulates the crosstalk of ACD and apoptosis will contribute to understanding the molecular mechanism of PCD in NSCs. ⓒ 2015 DGIST