Effect of the cross‐talk between autophagy and endoplasmic reticulum stress on Mn‐induced alpha‐synuclein oligomerization

Abstract Overexposure to manganese (Mn) has been known to induce alpha‐synuclein (α‐Syn) oligomerization, which is degraded mainly depending on endoplasmic reticulum stress (ER stress) and autophagy pathways. However, little data reported the cross‐talk between ER stress and autophagy on Mn‐induced α‐Syn oligomerization. To explore the relationship between ER stress and autophagy, we used 4‐phenylbutyric acid (4‐PBA, the ER stress inhibitor), rapamycin (Rap, autophagy activator) and 3‐methyladenine (3‐MA, autophagy inhibitor) in mice model of manganism. After 4 weeks of treatment with Mn, both ER stress and autophagy were activated. Exposed to Mn also resulted in α‐Syn oligomerization and neuronal cell damage in the brain tissue of mice, which could be relieved by 4‐PBA pretreatment. Moreover, when the ER stress was inhibited, the activation of autophagy was also inhibited. Rap pretreatment significantly activated autophagy and decreased α‐Syn oligomers. However, 3‐MA pretreatment inhibited autophagy resulting in increase of α‐Syn oligomers, and compensatorily activated PERK signaling pathway. Our results also demonstrated that the inhibition of autophagy by 3‐MA aggravated neuronal cell damage. The findings clearly demonstrated that the cross‐talking between autophagy and ER stress might play an important role in the α‐Syn oligomerization and neurotoxicity by Mn.