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Manganese (Mn), an essential micronutrient, acts as a cofactor for multiple enzymes. Epidemiological investigations have shown that an excessive level of Mn is an important environmental factor involved in neurotoxicity. Frequent pollution of air and water by Mn is a serious threat to the health of the population. Overexposure to Mn is particularly detrimental to the central nervous system, leading to symptoms similar to several neurological disorders. Many different mechanisms have been implicated in Mn-induced neurotoxicity, including oxidative/nitrosative stress, toxic protein aggregation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, dysregulation of autophagy, and the apoptotic cascade, which together promote the progressive neurodegeneration of nerve cells. As a compensatory regulatory mechanism, autophagy plays dual roles in various biological activities under pathological stress conditions. Dysregulation of autophagy is involved in the development of neurodegenerative disorders, with recent emerging evidence indicating a strong, complex relationship between autophagy and Mn-induced neurotoxicity. This review discusses the connection between autophagy and Mn-induced neurotoxicity, especially alpha-synuclein oligomerization, ER stress, and aberrated protein S-nitrosylation, which will provide new insights to profoundly explore the precise mechanisms of Mn-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Overexposure to manganese (Mn) has been known to induce nitrosative stress. The dysregulation of autophagy has implicated in nitric oxide (NO) bioactivity alterations. However, the mechanism of Mn-induced autophagic dysregulation is unclear. The protein of Bcl-2 was considered as a key role that could participate to the autophagy signaling regulation. To further explore whether S-nitrosylation of Bcl-2 involved in Mn-induced autophagy dysregulation, we treated human neuroblastoma (SH-SY5Y) cells with Mn and pretreated cells with 1400 W, a selective iNOS inhibitor. After cells were treated with 400 μM Mn for 24 h, there were significant increases in production of NO, inducible NO synthase (iNOS) activity, the mRNA and protein expressions of iNOS. Interestingly, autophagy was activated after cells were treated with Mn for 0-12 h; while the degradation process of autophagy-lysosome pathway was blocked after cells were treated with Mn for 24 h. Moreover, S-nitrosylated JNK and Bcl-2 also increased and phospho-JNK and phospho-Bcl-2 reduced in Mn-treated cells. Then, the affinity between Bcl-2 and Beclin-1 increased significantly in Mn-treated cells. We used the 1400 W to neutralize Mn-induced nitrosative stress. The results showed that S-nitrosylated JNK and Bcl-2 reduced while their phosphorylation were recovered to some extent. The findings revealed that NO-mediated S-nitrosylation of Bcl-2 directly affected the interaction between Beclin-1 and Bcl-2 leading to autophagy inhibition. [ABSTRACT FROM AUTHOR]