Ethanol promotes endoplasmic reticulum stress-induced neuronal death: Involvement of oxidative stress

Gang Chen, Cuiling Ma, Kimberly A. Bower, Xianglin Shi, Zunji Ke, Jia Luo

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

One of the most devastating effects of ethanol exposure during development is the loss of neurons in selected brain areas. The underlying cellular/molecular mechanisms remain unclear. The endoplasmic reticulum (ER) is involved in posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress, which is characterized by translational attenuation, synthesis of ER chaperone proteins such as GRP78, and activation of transcription factors such as ATF4, ATF6, and CHOR Sustained ER stress ultimately leads to cell death. ER stress response can be induced experimentally by treatment with tunicamycin and thapsigargin. Using SH-SY5Y neuroblastoma cells and primary cerebellar granule neurons as in vitro models, we demonstrated that exposure to ethanol alone had little effect on the expression of markers for ER stress; however, ethanol drastically enhanced the expression of GRP78, CHOP, ATF4, ATF6, and phosphorylated PERK and elF2α when induced by tunicamycin and thapsigargin. Consistently, ethanol promoted tunicamycin- and thapsigargin-induced cell death. Ethanol rapidly caused oxidative stress in cultured neuronal cells; antioxidants blocked ethanol's potentiation of ER stress and cell death, suggesting that the ethanol-promoted ER stress response is mediated by oxidative stress. CHOP is a proapoptotic transcription factor. We further demonstrated that CHOP played an important role in ethanol-promoted cell death. Thus, the effect of ethanol may be mediated by the interaction between oxidative stress and ER stress.

Original languageEnglish
Pages (from-to)937-946
Number of pages10
JournalJournal of Neuroscience Research
Volume86
Issue number4
DOIs
StatePublished - Mar 2008

Keywords

  • Alcohol
  • Apoptosis
  • Cerebellum
  • Development
  • Fetal alcohol syndrome

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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