Elevating sestrin2 attenuates endoplasmic reticulum stress and improves functional recovery through autophagy activation after spinal cord injury

Abstract Background Spinal cord injury (SCI) is a devastating central neurological trauma that causes a loss of motor and sensory function. Sestrin2, also known as hypoxia inducible gene 95 (Hi95), is emerging as a critical determinant of cell homeostasis in response to cellular stress. However, the role of sestrin2 in neuron response to endoplasmic reticulum (ER) stress and potential mechanism remains undefined. In this study, we investigated the effects of sestrin2 on ER stress and delineated a underlying molecular mechanism after SCI. Methods The induction of sestrin2 after traumatic injury and ER stress insult were investigated in vitro and in vivo. West blot and immunofluorescence were used to analyze the potential mechanisms of sestrin2 on autophagy and ER stress after SCI. Behavior assessment were used to evaluated the effect of sestrin2 on function recovery in vivo. Results 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, overexpression of sestrin2 limits ER stress, promotes the survival of neuron and improves functional recovery after SCI, which is associated with activation of autophagy and restoration of autophagic flux mediated by sestrin2. Meanwhile, sestrin2 activates autophagy dependent on AMPK-mTOR signaling pathway. Consistently, inhibition of AMPK abrogates the effect of sestrin2 on activation of autophagy, and blockage of autophagic flux abolishes the effect of sestrin2 on limiting ER stress and neural death. Conclusion Upregulation of sestrin2 as an important resistance mechanism of neuron to ER stress, and its potential role as a therapeutic target for SCI.