Mn-Induced Neurocytes Injury and Autophagy Dysfunction in Alpha-Synuclein Wild-Type and Knock-Out Mice: Highlighting the Role of Alpha-Synuclein

Abstract

Overexposure to manganese (Mn) is an important environmental risk factor for Parkinsonian-like symptoms referred to as manganism. Alpha-synuclein (α-Syn) oligomerization is a major cause in Mn-induced neurotoxicity. Autophagy, as an adjust response to control intracellular protein homeostasis, is involved in the degradation of α-Syn monomers or oligomers. Furthermore, autophagy dysregulation is also related to development of neurodegenerative disorders. Hence, we speculated that there was an interaction effect between α-Syn oligomerization and autophagy upon Mn exposure. In this study, we applied α-Syn gene knockout mice (α-Syn^−/−) and wild-type mice (α-Syn^+/+) treated with three different concentrations of MnCl₂ (50, 100, and 200 μmol/kg) to elucidate the physiological role of α-Syn in Mn-induced autophagy dysregulation and neurocytes injury. We found that activation of chaperone-mediated autophagy (CMA) pathway by Mn was independent of α-Syn. Additionally, α-Syn could ameliorate excessive autophagy induced by high dose Mn (200 μmol/kg). Next, we used 5 mg/kg Rapamycin (Rap) or 3-methyladenine (3-MA) to regulate autophagy. The study revealed that autophagy is involved in Mn-induced α-Syn oligomerization and neurocytes injury. Taken together, these findings indicated that α-Syn oligomerization might be the major responsible for the Mn-induced autophagy dysregulation and neurocytes injury.

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