2020) Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits, Autophagy, 16:3, 512-530, ABSTRACT Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress-or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders.Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA 1 : bafilomycin A 1 ; BrdU: Bromodeoxyuridine/5-bromo-2ʹ

Carbon monoxide (CO) is well-known as toxic gas and intrinsic signaling molecule such as neurotransmitter and blood vessel relaxant. Recently, it has been reported that low concentration of CO exerts therapeutic actions under various pathological conditions including liver failure, heart failure, gastric cancer, and cardiac arrest. However, little has been known about the effect of CO in neurodegenerative diseases like Parkinson’s disease (PD). To test whether CO could exert a beneficial action during oxidative cell death in PD, we examined the effects of CO on 6-hydroxydopamine (6-OHDA)-induced cell death in C6 glioma cells. Treatment of CO-releasing molecule-2 (CORM-2) significantly attenuated 6-OHDA-induced apoptotic cell death in a dose-dependent manner. CORM-2 treatment decreased Bax/Bcl2 ratio and caspase-3 activity, which had been increased by 6-OHDA. CORM-2 increased phosphorylation of NF-E2-related factor 2 (Nrf2) which is a transcription factor regulating antioxidant proteins. Subsequently, CORM-2 also increased the expression of heme oxygenase-1 and superoxide dismutases (CuZnSOD and MnSOD), which were antioxidant enzymes regulated by Nrf2. These results suggest that CO released by CORM-2 treatment may have protective effects against oxidative cell death in PD through the potentiation of cellular adaptive survival responses via activation of Nrf2 and upregulation of heme oxygenase-1, leading to increasing antioxidant defense capacity.

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