Journal article
Ethanol Promotes Thiamine Deficiency-Induced Neuronal Death: Involvement of Double-Stranded RNA-activated Protein Kinase
Alcoholism, clinical and experimental research, Vol.33(6), pp.1097-1103
Received for publication November 10, 2008; accepted January 30, 2009.
06/2009
DOI: 10.1111/j.1530-0277.2009.00931.x
PMCID: PMC3093711
PMID: 19382901
Abstract
Background: Heavy alcohol consumption causes cerebellar degeneration, and the underlying mechanism is unclear. Chronic alcoholism is usually associated with thiamine deficiency (TD) which is known to induce selective neurodegeneration in the brain. However, the role of TD in alcohol-induced cerebellar degeneration remains to be elucidated. The double-stranded RNA-activated protein kinase (PKR) is a potent antiviral protein. Viral infection or binding to dsRNA causes PKR autophosphorylation and subsequent phosphorylation of the alpha-subunit of eukaryotic translation factor-2alpha, leading to inhibition of translation or apoptosis. PKR can also be activated by cellular stresses.
Methods: In this study, we used an in vitro model, cultured cerebellar granule neurons (CGNs), to investigate the interaction between TD and ethanol and evaluate the contribution of their interaction to neuronal loss. TD was induced by treatment with amprolium in association with ethanol. Cell viability was determined by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay. PKR expression/phosphorylation and subcellular distribution was analyzed with immunoblotting and immunocytochemistry.
Results: Thiamine deficiency caused death of CGNs but ethanol did not. However, TD plus ethanol induced a much greater cell loss than TD alone. TD-induced PKR phosphorylation and ethanol exposure significantly promoted TD-induced PKR phosphorylation as well as its nuclear translocation. A selective PKR inhibitor not only protected CGNs against TD toxicity, but also abolished ethanol potentiation of TD-induced loss of CGNs.
Conclusions: Ethanol promoted TD-induced PKR activation and neuronal death. PKR may be a convergent protein that mediates the interaction between TD and ethanol.
Details
- Title: Subtitle
- Ethanol Promotes Thiamine Deficiency-Induced Neuronal Death: Involvement of Double-Stranded RNA-activated Protein Kinase
- Creators
- Zun-Ji Ke - Shanghai Institutes for Biological SciencesXin Wang - University of KentuckyZhiqin Fan - Shanghai Institutes for Biological SciencesJia Luo - Shanghai Institutes for Biological Sciences
- Resource Type
- Journal article
- Publication Details
- Alcoholism, clinical and experimental research, Vol.33(6), pp.1097-1103
- Edition
- Received for publication November 10, 2008; accepted January 30, 2009.
- DOI
- 10.1111/j.1530-0277.2009.00931.x
- PMID
- 19382901
- PMCID
- PMC3093711
- NLM abbreviation
- Alcohol Clin Exp Res
- ISSN
- 0145-6008
- eISSN
- 1530-0277
- Publisher
- Blackwell Publishing Ltd
- Number of pages
- 7
- Language
- English
- Date published
- 06/2009
- Academic Unit
- Pathology
- Record Identifier
- 9984186438702771
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