Journal article
Autophagy is a protective response to ethanol neurotoxicity
Autophagy, Vol.8(11), pp.1577-1589
11/01/2012
DOI: 10.4161/auto.21376
PMCID: PMC3494588
PMID: 22874567
Abstract
Ethanol is a neuroteratogen and neurodegeneration is the most devastating consequence of developmental exposure to ethanol. The mechanisms underlying ethanol-induced neurodegeneration are complex. Ethanol exposure produces reactive oxygen species (ROS) which cause oxidative stress in the brain. We hypothesized that ethanol would activate autophagy to alleviate oxidative stress and neurotoxicity. Our results indicated that ethanol increased the level of the autophagic marker Map1lc3-II (LC3-II) and upregulated LC3 puncta in SH-SY5Y neuroblastoma cells. It also enhanced the levels of LC3-II and BECN1 in the developing brain; meanwhile, ethanol reduced SQSTM1 (p62) levels. Bafilomycin A
1
, an inhibitor of autophagosome and lysosome fusion, increased p62 levels in the presence of ethanol. Bafilomycin A
1
and rapamycin potentiated ethanol-increased LC3 lipidation, whereas wortmannin and a
BECN1
-specific shRNA inhibited ethanol-promoted LC3 lipidation. Ethanol increased mitophagy, which was also modulated by
BECN1
shRNA and rapamycin. The evidence suggested that ethanol promoted autophagic flux. Activation of autophagy by rapamycin reduced ethanol-induced ROS generation and ameliorated ethanol-induced neuronal death in vitro and in the developing brain, whereas inhibition of autophagy by wortmannin and
BECN1
-specific shRNA potentiated ethanol-induced ROS production and exacerbated ethanol neurotoxicity. Furthermore, ethanol inhibited the MTOR pathway and downregulation of MTOR offered neuroprotection. Taken together, the results suggest that autophagy activation is a neuroprotective response to alleviate ethanol toxicity. Ethanol modulation of autophagic activity may be mediated by the MTOR pathway.
Details
- Title: Subtitle
- Autophagy is a protective response to ethanol neurotoxicity
- Creators
- Gang Chen - University of KentuckyZunji Ke - University of KentuckyMei Xu - University of KentuckyMingjun Liao - University of KentuckyXin Wang - University of KentuckyYuanlin Qi - University of KentuckyTao Zhang - University of KentuckyJacqueline A Frank - University of KentuckyKimberly A Bower - University of KentuckyXianglin Shi - University of KentuckyJia Luo - University of Kentucky
- Resource Type
- Journal article
- Publication Details
- Autophagy, Vol.8(11), pp.1577-1589
- Publisher
- Landes Bioscience
- DOI
- 10.4161/auto.21376
- PMID
- 22874567
- PMCID
- PMC3494588
- ISSN
- 1554-8627
- eISSN
- 1554-8635
- Language
- English
- Date published
- 11/01/2012
- Academic Unit
- Pathology
- Record Identifier
- 9984201119202771
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