Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Endoplasmic reticulum stress and apoptosis induced by manganese trigger ^5;-synuclein accumulation

Hyonok Yoon^1,2, Geum Hwa Lee³, Bo Li³, Sunt Ah Park³, Seung-Jae Lee⁴, Han-Jung Chae²

¹College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju; ²Department of Life Style Medicine, Chonbuk National University, Jeonju; ³Department of Pharmacology and Cardiovascular Research Institute, Medical School, Seoul; ⁴Department of Biomedical Sciences and Neuroscience Research Institute and College of Medicine, Seoul National University, Seoul, Republic of Korea.

For correspondence:- Han-Jung Chae Email: hjchae@jbnu.ac.kr

Accepted: 21 July 2018 Published: 31 August 2018

Citation: Yoon H, Lee GH, Li B, Park SA, Lee S, Chae H. Endoplasmic reticulum stress and apoptosis induced by manganese trigger ^5;-synuclein accumulation. Trop J Pharm Res 2018; 17(8):1497-1503 doi: 10.4314/tjpr.v17i8.6

© 2018 The authors.
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Abstract

Purpose: To explore whether α-synuclein aggregation is linked to endoplasmic reticulum (ER) stress and apoptosis induced by manganese (Mn) on CATH.a dopaminergic cell lines.

Methods: Western blot analysis for the expression of 78 kDa glucose-regulated protein (GRP78), phosphorylated eukaryotic initiation factor 2α (p-eIF-2α), eIF2α, inositol requiring enzyme 1(IRE-1α), cleaved caspase-3, and C/EBP homologous protein (CHOP) was performed, including overexpression of recombinant adenovirus-mediated α-synuclein on CATH.a dopaminergic cell line.

Results: It was observed that cell viability (p < 0.05) was significantly reduced by 250 μM exposed for 3 h and 1,000 μM of MnCl₂ exposed for 24 h. The expression of p-elF-2α, IRE-1α, and GRP78 was especially induced by 1,000 μM of MnCl₂ exposed at 3, 6, and 12 h, respectively (p < 0.05). Twenty four-hour exposure of 250 uM of MnCl₂ and the 3 h exposure of 1,000 uM of MnCl₂ significantly induced CHOP, active caspase 3 and α-synuclein expression (p < 0.05). α-Synuclein combined with recombinant adenoviral transduction increased GRP78, IRE-1α and eIF2a, CHOP and caspase 3 expression at longer times and at higher concentrations of manganese exposure on CATH.a dopaminergic cells.

Conclusion: Based on these findings, Mn is a risk factor for diseases associated with α-synuclein accumulation. Furthermore, α-synuclein accumulation is associated with apoptosis via ER stress induced by Mn.

Keywords: Manganese (Mn), ^5;- Synuclein, Endoplasmic reticulum (ER) stress, Apoptosis