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

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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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Abbreviations

Mn:

Manganese

PD:

Parkinson’s disease

BBB:

Blood-brain barrier

CNS:

Central nervous system

α-Syn:

Alpha-synuclein

CMA:

Chaperone-mediated autophagy

Rap:

Rapamycin

3-MA:

3-Methyladenine

I.P.:

Intraperitoneal

S.C.:

Subcutaneously

MDC:

Monodansylcadaverine

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Funding

This work was supported by the National Natural Science Foundation of China (81773377).

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Authors and Affiliations

  1. Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People’s Republic of China

    Dong-Ying Yan, Chang Liu, Xuan Tan, Zhuo Ma, Can Wang, Yu Deng, Wei Liu, Zhao-Fa Xu & Bin Xu

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  1. Dong-Ying Yan
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  2. Chang Liu
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  3. Xuan Tan
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  4. Zhuo Ma
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  5. Can Wang
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  7. Wei Liu
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  8. Zhao-Fa Xu
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  9. Bin Xu
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Correspondence to Bin Xu.

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Animal treatment and care were in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and approved by the Animal Ethical Committee of China Medical University.

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Yan, DY., Liu, C., Tan, X. et al. Mn-Induced Neurocytes Injury and Autophagy Dysfunction in Alpha-Synuclein Wild-Type and Knock-Out Mice: Highlighting the Role of Alpha-Synuclein. Neurotox Res 36, 66–80 (2019). https://doi.org/10.1007/s12640-019-00016-y

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  • DOI: https://doi.org/10.1007/s12640-019-00016-y

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