FAIM2 stability controls the balance of cell death and survival in adult neural stem cells by regulating autophagy

Abstract

Adult neural stem cells maintain self-renewal capacity and multipotency in the adult brain, thus regulating the output of neurogenesis. Autophagy thought to play a pro-survival role in the cells can kill cells as we have previously shown that autophagic cell death (ACD) is a dominant programmed cell death mode in adult hippocampal neural stem cells subjected to insulin withdrawal in vitro. In postnatal mouse hippocampus, Fas apoptotic inhibitory molecule 2 (FAIM2) gradually increases with age. We found that FAIM2 is expressed in adult hippocampal neural stem cells. Decrease in FAIM2 protein is accompanied by ACD following insulin withdrawal. Prevention of protein synthesis by cyclohexamide showed shorter half-life of FAIM2 in ACD in comparison to that in basal state. Indeed, FAIM2 was post-translationally degraded via autophago-lysosomal pathway. FAIM2 knockdown via siRNA augmented cell death and increased autophagy markers. In summary, our result suggests that FAIM2 protein stability is a critical determinant of neural stem cells’ susceptibility to ACD. Our results expand the role of FAIM2, which was previously established as a neuron-specific anti-apoptotic protein, to regulation of autophagy in neural stem cells.