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Alpha-Synuclein Oligomerization in Manganese-Induced Nerve Cell Injury in Brain Slices: A Role of NO-Mediated S-Nitrosylation of Protein Disulfide Isomerase

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Abstract

Over-exposure to manganese (Mn) has been known to induce endoplasmic reticulum (ER) stress involving protein misfolding. The proper maturation and folding of native proteins rely on the activity of protein disulfide isomerase (PDI). However, the exact mechanism of Mn-induced alpha-synuclein oligomerization is unclear. To explore whether alpha-synuclein oligomerization was associated with S-nitrosylation of PDI, we made the rat brain slice model of manganism and pretreated slices with l-Canavanine, a selective iNOS inhibitor. After slices were treated with Mn (0, 25, 100, and 400 μM) for 24 h, there were dose-dependent increases in apoptotic percentage of cells, lactate dehydrogenase (LDH) releases, production of NO, inducible nitric oxide synthase (iNOS) activity, the mRNA and protein expressions of iNOS, and PDI. Moreover, S-nitrosylated PDI and alpha-synuclein oligomerization also increased. However, there was a significant increase in the PDI activity of 25-μM Mn-treated slices. Then, PDI activity and the affinity between PDI and alpha-synuclein decreased significantly in response to Mn (100 and 400 μM), which was associated with S-nitrosylation of PDI. The results indicated that S-nitrosylated PDI could affect its activity. We use the l-Canavanine pretreatment brain slices to inhibit S-nitrosylation of PDI. The results showed that l-Canavanine pretreatment could reduce Mn-induced nerve cell injury and alpha-synuclein oligomerization. Additionally, there was a significant recovery in PDI activity in l-Canavanine-pretreated slices. The findings revealed that Mn induced nitrosative stress via the activation of iNOS and subsequent S-nitrosylation of PDI in cultured slices. Moreover, S-nitrosylation of PDI is an important signaling event in the Mn-induced alpha-synuclein oligomerization in brain slices.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Grant no. 81102098).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110001, People’s Republic of China

    Bin Xu, Yu Deng, Wei Liu, Tian-Yao Yang, Shu Feng & Zhao-Fa Xu

  2. Department of Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China

    Cui-Hong Jin

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  1. Bin Xu
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  2. Cui-Hong Jin
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  4. Wei Liu
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Correspondence to Bin Xu.

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Xu, B., Jin, CH., Deng, Y. et al. Alpha-Synuclein Oligomerization in Manganese-Induced Nerve Cell Injury in Brain Slices: A Role of NO-Mediated S-Nitrosylation of Protein Disulfide Isomerase. Mol Neurobiol 50, 1098–1110 (2014). https://doi.org/10.1007/s12035-014-8711-z

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