Correlation Between Attenuation of Protein Disulfide Isomerase Activity Through S-Mercuration and Neurotoxicity Induced by Methylmercury

Kento Makino, Kosaku Okuda, Eisuke Sugino, Tadashi Nishiya, Takashi Toyama, Takao Iwawaki, Masatake Fujimura, Yoshito Kumagai, Takashi Uehara

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Methylmercury (MeHg), an environmental pollutant, causes neuronal death via endoplasmic reticulum (ER) stress; however, the precise mechanism is not fully understood. The aim of this study was to elucidate the possible mechanism of MeHg-induced neurotoxicity. Treatment with MeHg resulted in a loss of cell viability in a concentration-dependent manner accompanying the expression of ER stress marker genes in human neuroblastoma SH-SY5Y cells. We next attempted to identify a target protein for MeHg in the ER. MeHg covalently modified protein disulfide isomerase (PDI), which is important for disulfide bond formation in nascent proteins in the ER lumen. S-Nitrosylation of the catalytic domains of PDI by nitric oxide was attenuated up to 50 % by a MeHg challenge in cells. The MeHg-modified C-terminal catalytic domain in PDI was detected by MALDI-TOF/MS. Furthermore, treatment with MeHg significantly attenuated the enzymatic activity of PDI. Taken together, these observations suggest that MeHg results in ER stress and following the unfolded protein response pathway via ER dysfunction due to S-mercuration of the C-terminus of PDI.

Original languageEnglish
Pages (from-to)99-105
Number of pages7
JournalNeurotoxicity Research
Volume27
Issue number2
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Endoplasmic reticulum stress
  • Methylmercury
  • Neurotoxicity
  • Protein disulfide isomerase
  • S-mercuration

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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