Abstract
Spinal cord injury (SCI) is a devastating neurological trauma that causes losses of motor and sensory function. Sestrin2, also known as hypoxia inducible gene 95, is emerging as a critical determinant of cell homeostasis in response to cellular stress. However, the role of sestrin2 in the neuronal response to endoplasmic reticulum (ER) stress and the potential mechanism remain undefined. In this study, we investigated the effects of sestrin2 on ER stress and delineated an underlying molecular mechanism after SCI. Here, we found that elevated sestrin2 is a protective process in neurons against chemical ER stress induced by tunicamycin (TM) or traumatic invasion, while treatment with PERK inhibitor or knockdown of ATF4 reduces sestrin2 expression upon ER stress. In addition, we demonstrated that overexpression of sestrin2 limits ER stress, promoting neuronal survival and improving functional recovery after SCI, which is associated with activation of autophagy and restoration of autophagic flux mediated by sestrin2. Moreover, we also found that sestrin2 activates autophagy dependent on the AMPK-mTOR signaling pathway. Consistently, inhibition of AMPK abrogates the effect of sestrin2 on the activation of autophagy, and blockage of autophagic flux abolishes the effect of sestrin2 on limiting ER stress and neural death. Together, our data reveal that upregulation of sestrin2 is an important resistance mechanism of neurons to ER stress and the potential role of sestrin2 as a therapeutic target for SCI.
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Funding
This work was supported by grants from Natural Science Foundation of China (81722028, 81972150), Zhejiang Public Service Technology Research Program and Social Development (LGF18H060008), Natural Science Foundation of Zhejiang.
Province (LR18H50001, LQ18H090008), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-028).
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Yao Li designed the research and wrote the paper; Jing Zhang and Kailiang Zhou assisted in performing the in vivo and in vitro experiments; Ling Xie, Guangheng Xiang, and Mingqiao Fang guided the experiments and image acquisition; Wen Han modified the syntax of the paper; Xiangyang Wang and Xiao Jian assisted in designing the research and approved the final version to be submitted.
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Li, Y., Zhang, J., Zhou, K. et al. Elevating sestrin2 attenuates endoplasmic reticulum stress and improves functional recovery through autophagy activation after spinal cord injury. Cell Biol Toxicol 37, 401–419 (2021). https://doi.org/10.1007/s10565-020-09550-4
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DOI: https://doi.org/10.1007/s10565-020-09550-4