Abstract
Overexposure to manganese (Mn) is neurotoxic. Our previous research has demonstrated that the interaction of endoplasmic reticulum (ER) stress and autophagy participates in the early stage of Mn-mediated neurotoxicity in mouse. However, the mechanisms of ER stress signalling pathways in the initiation of autophagy remain confused. In the current study, we first validated that ER stress-mediated cell apoptosis is accompanied by autophagy in SH-SY5Y cells. Then, we found that inhibiting ER stress with 4-phenylbutyrate (4-PBA) decreased ER stress-related protein expression and reduced cell apoptosis, whereas blocking autophagy with 3-methyladenine (3-MA) increased cell apoptosis. These data indicate that protective autophagy was activated to alleviate ER stress-mediated apoptosis. Knockdown of the protein kinase RNA-like ER kinase (PERK) gene inhibited Mn-induced autophagy and weakened the interaction between ATF4 and the LC3 promoter. Our results reveal a novel molecular mechanism in which ER stress may regulate autophagy via the PERK/eIF2α/ATF4 signalling pathway. Additionally, Mn may activate protective autophagy to alleviate ER stress-mediated apoptosis via the PERK/eIF2α/ATF4 signalling pathway in SH-SY5Y cells.