Elevating sestrin2 attenuates endoplasmic reticulum stress and improves functional recovery through autophagy...

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. Graphical abstract.