Syntaxin 17 inhibits ischemic neuronal injury by resuming autophagy flux and ameliorating endoplasmic reticulum stress

Abstract

Previous studies have shown that syntaxin 17 (STX17) is involved in mediating the fusion of autophagosomes and lysosomes. This study aimed to investigate the role and mechanism of STX17 in neuronal injury following cerebral ischemia/reperfusion. The ischemia/reperfusion (I/R) models were established by transient middle cerebral artery occlusion (tMCAO) in mice and oxygen glucose deprivation/reperfusion (O/R) in primary cultured cortical neurons and HT22 cells. Cerebral ischemia/reperfusion significantly up-regulated the expression of STX17 in neurons. Lentivirus mediated knockdown of STX17 in neurons reduced neuronal viability and increased LDH leakage. Injection of AAV9-shSTX17 into the brain of mice then subjected to tMCAO also significantly augmented the infarct area and exacerbated neurobehavioral deficits and mortality. Depletion of STX17 caused accumulation of autophagic marker/substrate LC3 II and p62, blockade of the autophagic flux, and the accumulation of dysfunctional lysosomes. Knockdown of STX17 also aggravated endoplasmic reticulum (ER) stress-dependent neuronal apoptosis induced by ischemia/reperfusion. Importantly, induction of autophagy-lysosomal pathway and alleviation of ER stress partially rescued STX17 knockdown-induced neuronal damage. These results suggest that STX17 may ameliorate ischemia/reperfusion-induced neuronal damage by enhancing autophagy flux and reducing ER stress-dependent neuronal apoptosis.