ER stress mediated-autophagy contributes to neurological dysfunction in traumatic brain injury via the ATF6 UPR signaling pathway

A major public health problem, traumatic brain injury (TBI) can cause severe neurological impairment. Although autophagy is closely associated with the pathogenesis of TBI, the role of autophagy in neurological deficits is unclear. The purpose of the present study was to investigate the molecular mechanisms of endoplasmic reticulum (ER) stress-induced autophagy and its detrimental effects on neurological outcomes following TBI. A rat model of TBI was established by controlled cortical impact. ER stress activation, autophagy induction and autophagic flux dysfunction were examined in the damaged hippocampus post-TBI. Pharmacological inhibition of ER stress significantly blocked post-traumatic autophagy activation, as evidenced by decreased conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II and Beclin-1 expression levels in the hippocampus region. Short hairpin RNA-mediated activating transcription factor 6 knockdown significantly prevented ER stress-mediated autophagy stimulation via targeting essential autophagic genes, including autophagy related (ATG)3, ATG9 and ATG12. Furthermore, neurological scores, foot fault test and Morris water maze were used to evaluate the neurological functions of TBI rats. The results revealed that the blockage of ER stress or autophagy attenuated TBI-induced traumatic damage and functional outcomes. In conclusion, these findings provided new insights into the molecular mechanisms of ER stress-induced autophagy and demonstrated its potential role in neurological deficiency following TBI.