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Overexposure to manganese (Mn) is widely known to induce alpha‐synuclein (α‐Syn) oligomerization, which has been attributed to the oxidative damage of α‐Syn protein. Trehalose has been shown to induce autophagy and serve as a chemical chaperone, but little information has been reported about its effect on Mn‐induced α‐Syn oligomerization. In this study, we investigate whether trehalose can effectively interfere with Mn‐induced α‐Syn oligomerization, using different concentrations of trehalose (2% and 4% (g/vol [mL])) in a mouse model of manganism. After 6 weeks of exposure to Mn, both oxidative stress and autophagy were activated and resulted in α‐Syn oligomerization and neuronal cell damage in the mouse brain tissue. Our results also revealed that pretreatment with trehalose significantly reduced the oxidative damage to α‐Syn protein and increased autophagy activation. These findings clearly demonstrated that trehalose can relieve Mn‐induced α‐Syn oligomerization and neuronal cell damage through its anti‐oxidative and autophagy‐inducing effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]