Abstract
Neuroimaging and post-mortem studies indicate that chronic alcohol use induces global changes in brain morphology, such as cortical and subcortical atrophy. Recent studies have shown that frontal lobe structures are specifically susceptible to alcohol-related brain damage and shrinkage in this area is largely due to a loss of white matter. This may explain the high incidence of cognitive dysfunction observed in alcoholics. Using a proteomics-based approach, changes in protein expression in the dorsolateral prefrontal region (BA9) white matter were identified in human alcoholic brains. Protein extracts from the BA9 white matter of 25 human brains (10 controls; eight uncomplicated alcoholics; six alcoholics complicated with hepatic cirrhosis; one reformed alcoholic) were separated using two-dimensional gel electrophoresis. Overall, changes in the relative expression of 60 proteins were identified (P<0.05, ANOVA) in the alcoholic BA9 white matter. In total, 18 protein spots have been identified using MALDI-TOF; including hNP22, α-internexin, transketolase, creatine kinase chain B, ubiquitin carboxy-terminal hydrolase L1 and glyceraldehyde-3-phosphate dehydrogenase. Several of these proteins have been previously implicated in alcohol-related disorders and brain damage. By identifying changes in protein expression in this region from alcoholics, hypotheses may draw upon more mechanistic explanations as to how chronic ethanol consumption causes white matter damage.
Similar content being viewed by others
References
Harper C, Kril J . An introduction to alcohol-induced brain damage and its causes. Alcohol Alcohol Suppl 1994; 2: 237–243.
Pfefferbaum A, Lim KO, Zipursky RB, Mathalon DH, Rosenbloom MJ, Lane B et al. Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: a quantitative MRI study. Alcohol Clin Exp Res 1992; 16: 1078–1089.
Pfefferbaum A, Rosenbloom M, Crusan K, Jernigan TL . Brain CT changes in alcoholics: effects of age and alcohol consumption. Alcohol Clin Exp Res 1988; 12: 81–87.
Pishkin V, Lovallo WR, Bourne Jr LE . Chronic alcoholism in males: cognitive deficit as a function of age of onset, age, and duration. Alcohol Clin Exp Res 1985; 9: 400–406.
Dao-Castellana MH, Samson Y, Legault F, Martinot JL, Aubin HJ, Crouzel C et al. Frontal dysfunction in neurologically normal chronic alcoholic subjects: metabolic and neuropsychological findings. Psychol Med 1998; 28: 1039–1048.
Adams KM, Gilman S, Koeppe RA, Kluin KJ, Brunberg JA, Dede D et al. Neuropsychological deficits are correlated with frontal hypometabolism in positron emission tomography studies of older alcoholic patients. Alcohol Clin Exp Res 1993; 17: 205–210.
Harper C, Dixon G, Sheedy D, Garrick TM . Neuropathological alterations in alcoholic brains. Studies arising from the New South Wales Tissue Resource Centre. Prog Neuropsycopharmacol Biol Psychiatry 2003; 27: 951–961.
Carlen PL, Wortzman G, Holgate RC, Wilkinson DA, Rankin JC . Reversible cerebral atrophy in recently abstinent chronic alcoholics measured by computed tomography scans. Science 1978; 200: 1076–1078.
Harper C . The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain? J Neuropathol Exp Neurol 1998; 57: 101–110.
Kril JJ, Halliday GM, Svoboda MD, Cartwright H . The cerebral cortex is damaged in chronic alcoholics. Neuroscience 1997; 79: 983–998.
Schweinsburg BC, Taylor MJ, Alhassoon OM, Videen JS, Brown GG, Patterson TL et al. Chemical pathology in brain white matter of recently detoxified alcoholics: a 1H magnetic resonance spectroscopy investigation of alcohol-associated frontal lobe injury. Alcohol Clin Exp Res 2001; 25: 924–934.
Harper C, Matsumoto I . Ethanol and brain damage. Curr Opin Pharmacol 2005; 5: 73–78.
Mayfield RD, Lewohl JM, Dodd PR, Herlihy A, Liu J, Harris RA . Patterns of gene expression are altered in the frontal and motor cortices of human alcoholics. J Neurochem 2002; 81: 802–813.
Gygi SP, Rochon Y, Franza BR, Aebersold R . Correlation between protein and mRNA abundance in yeast. Mol Cell Biol 1999; 19: 1720–1730.
Anderson L, Seilhamer J . A comparison of selected mRNA and protein abundances in human liver. Electrophoresis 1997; 18: 533–537.
Lewohl JM, Van Dyk DD, Craft GE, Innes DJ, Mayfield RD, Cobon G et al. The application of proteomics to the human alcoholic brain. Ann NY Acad Sci 2004; 1025: 14–26.
Tooney PA, Chahl LA . Neurons expressing calcium-binding proteins in the prefrontal cortex in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 273–278.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. The Association: Washington, DC, 1994.
Bradford MM . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248–254.
Hoffman PL, Miles M, Edenberg HJ, Sommer W, Tabakoff B, Wehner JM et al. Gene expression in brain: a window on ethanol dependence, neuroadaptation, and preference. Alcohol Clin Exp Res 2003; 27: 155–168.
Fonseca LL, Alves PM, Carrondo MJ, Santos H . Effect of ethanol on the metabolism of primary astrocytes studied by (13)C- and (31)P-NMR spectroscopy. J Neurosci Res 2001; 66: 803–811.
Lamarche F, Gonthier B, Signorini N, Eysseric H, Barret L . Acute exposure of cultured neurones to ethanol results in reversible DNA single-strand breaks; whereas chronic exposure causes loss of cell viability. Alcohol Alcohol 2003; 38: 550–558.
Brooks PJ . DNA damage, DNA repair, and alcohol toxicity--a review. Alcohol Clin Exp Res 1997; 21: 1073–1082.
Singh NP, Lai H, Khan A . Ethanol-induced single-strand DNA breaks in rat brain cells. Mutat Res 1995; 345: 191–196.
Ikegami Y, Goodenough S, Inoue Y, Dodd PR, Wilce PA, Matsumoto I . Increased TUNEL positive cells in human alcoholic brains. Neurosci Lett 2003; 349: 201–205.
Castegna A, Aksenov M, Aksenova M, Thongboonkerd V, Klein JB, Pierce WM et al. Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1. Free Radical Biol Med 2002; 33: 562–571.
Kurihara LJ, Kikuchi T, Wada K, Tilghman SM . Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia. Hum Mol Genet 2001; 10: 1963–1970.
Hemmer W, Wallimann T . Functional aspects of creatine kinase in brain. Dev Neurosci 1993; 15: 249–260.
Kasparova S, Dobrota D, Mlynarik V, Pham TN, Liptaj T, Horecky J et al. A study of creatine kinase reaction in rat brain under chronic pathological conditions-chronic ischemia and ethanol intoxication. Brain Res Bull 2000; 53: 431–435.
Fan L, Jaquet V, Dodd PR, Chen W, Wilce PA . Molecular cloning and characterization of hNP22: a gene up-regulated in human alcoholic brain. J Neurochem 2001; 76: 1275–1281.
de las Heras R, Leah J, Kroon PA, Wilce WA . Process formation induced by human neuronal protein of 22 kDa, hNP22. In: Proceedings of the Australian Neuroscience Society, 14:Pos-Thu-086 2003.
Depaz I, Ito M, Matsumoto I, Niwa S, Kroon P, Wilce PA . Expression of hNP22 is altered in the frontal cortex and hippocampus of the alcoholic human brain. Alcohol Clin Exp Res 2003; 27: 1481–1488.
Lariviere RC, Julien JP . Functions of intermediate filaments in neuronal development and disease. J Neurobiol 2004; 58: 131–148.
Liu Q, Xie F, Siedlak SL, Nunomura A, Honda K, Moreira PI et al. Neurofilament proteins in neurodegenerative diseases. Cell Mol Life Sci 2004; 61: 3057–3075.
Martin PR, Pekovich SR, McCool BA, Whetsell WO, Singleton CK . Thiamine utilization in the pathogenesis of alcohol-induced brain damage. Alcohol Alcohol Suppl 1994; 2: 273–279.
Harper C . Wernicke's encephalopathy: a more common disease than realized. A neuropathological study of 51 cases. J Neurol Neurosurg Psychiatry 1979; 42: 226–231.
McCool BA, Plonk SG, Martin PR, Singleton CK . Cloning of human transketolase cDNAs and comparison of the nucleotide sequence of the coding region in Wernicke-Korsakoff and non-Wernicke-Korsakoff individuals. J Biol Chem 1993; 268: 1397–1404.
Wang JJ, Martin PR, Singleton CK . A transketolase assembly defect in a Wernicke-Korsakoff syndrome patient. Alcohol Clin Exp Res 1997; 21: 576–580.
Morgan MY . Alcohol and nutrition. Br Med Bull 1982; 38: 21–29.
Camilo ME, Morgan MY, Sherlock S . Erythrocyte transketolase activity in alcoholic liver disease. Scand J Gastroenterol 1981; 16: 273–279.
Harper CG, Sheedy DL, Lara AI, Garrick TM, Hilton JM, Raisanen J . Prevalence of Wernicke-Korsakoff syndrome in Australia: has thiamine fortification made a difference? Med J Aust 1998; 168: 542–545.
Olah J, Orosz F, Keseru GM, Kovari Z, Kovacs J, Hollan S et al. Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease. Biochem Soc Trans 2002; 30: 30–38.
Sirover MA . Role of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in normal cell function and in cell pathology. J Cell Biochem 1997; 66: 133–140.
Berry MD, Boulton AA . Glyceraldehyde-3-phosphate dehydrogenase and apoptosis. J Neurosci Res 2000; 60: 150–154.
Sirover MA . New insights into an old protein: the functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase. Biochim Biophys Acta 1999; 1432: 159–184.
Chen W, Hardy P, Wilce PA . Differential expression of mitochondrial NADH dehydrogenase in ethanol-treated rat brain: revealed by differential display. Alcohol Clin Exp Res 1997; 21: 1053–1056.
Edlund C, Soderberg M, Kristensson K, Dallner G . Ubiquinone, dolichol, and cholesterol metabolism in aging and Alzheimer's disease. Biochem Cell Biol 1992; 70: 422–428.
Hamajima N, Tajima K, Morishita M, Hyodo C, Sakakibara N, Kawai C et al. Patients' expectations of information provided at cancer hospitals in Japan. Jpn J Clin Oncol 1996; 26: 362–367.
Castegna A, Aksenov M, Thongboonkerd V, Klein JB, Pierce WM, Booze R et al. Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part II: dihydropyrimidinase-related protein 2, alpha-enolase and heat shock cognate 71. J Neurochem 2002; 82: 1524–1532.
Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF et al. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry 2000; 5: 142–149.
Weitzdoerfer R, Fountoulakis M, Lubec G . Aberrant expression of dihydropyrimidinase related proteins-2,-3 and -4 in fetal Down syndrome brain. J Neural Transm Suppl 2001; 61: 95–107.
Franzen B, Yang Y, Sunnemark D, Wickman M, Ottervald J, Oppermann M et al. Dihydropyrimidinase related protein-2 as a biomarker for temperature and time dependent post mortem changes in the mouse brain proteome. Proteomics 2003; 3: 1920–1929.
Fountoulakis M, Hardmeier R, Hoger H, Lubec G . Postmortem changes in the level of brain proteins. Exp Neurol 2001; 167: 86–94.
Wang Y, Floor E . Hydrogen peroxide inhibits the vacuolar H+-ATPase in brain synaptic vesicles at micromolar concentrations. J Neurochem 1998; 70: 646–652.
Sun AY, Sun GY . Ethanol and oxidative mechanisms in the brain. J Biomed Sci 2001; 8: 37–43.
Sakai T . Biomarkers of lead exposure. Ind Health 2000; 38: 127–142.
Moore MR, Beattie AD, Thompson GG, Goldberg A . Depression of delta-aminolevulinic acid dehydratase activity by ethanol in man and rat. Clin Sci 1971; 40: 81–88.
Butterworth RF . Pathophysiology of alcoholic brain damage: synergistic effects of ethanol, thiamine deficiency and alcoholic liver disease. Metab Brain Dis 1995; 10: 1–8.
O'Neill J, Cardenas VA, Meyerhoff DJ . Effects of abstinence on the brain: quantitative magnetic resonance imaging and magnetic resonance spectroscopic imaging in chronic alcohol abuse. Alcohol Clin Exp Res 2001; 25: 1673–1682.
Estilaei MR, Matson GB, Payne GS, Leach MO, Fein G, Meyerhoff DJ . Effects of abstinence from alcohol on the broad phospholipid signal in human brain: an in vivo 31P magnetic resonance spectroscopy study. Alcohol Clin Exp Res 2001; 25: 1213–1220.
Acknowledgements
Tissues were received from the NSW Tissue Resource Centre, which is supported by the University of Sydney, Neuroscience Institute of Schizophrenia and Allied Disorders, National Institute of Alcohol Abuse and Alcoholism and NSW Department of Health. We thank Ms Therese Garrick and Ms Alisa Green for their advice and the Biomedical Mass Spectrometry Facility, University of New South Wales for their technical assistance. This work was supported by grants of the NSW Government BioFirst Award and Australian Brewer's Foundation, provided to IM. KA is an Australian Postgraduate Award holder.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Alexander-Kaufman, K., James, G., Sheedy, D. et al. Differential protein expression in the prefrontal white matter of human alcoholics: a proteomics study. Mol Psychiatry 11, 56–65 (2006). https://doi.org/10.1038/sj.mp.4001741
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4001741
- Springer Nature Limited
Keywords
This article is cited by
-
Brain proteomic atlas of alcohol use disorder in adult males
Translational Psychiatry (2023)
-
Exposure of Rat Neural Stem Cells to Ethanol Affects Cell Numbers and Alters Expression of 28 Proteins
Neurochemical Research (2018)
-
Clinical and pathological features of alcohol-related brain damage
Nature Reviews Neurology (2011)
-
Genes and Pathways Co-associated with the Exposure to Multiple Drugs of Abuse, Including Alcohol, Amphetamine/Methamphetamine, Cocaine, Marijuana, Morphine, and/or Nicotine: a Review of Proteomics Analyses
Molecular Neurobiology (2011)
-
Ethanol Increases TIEG2–MAO B Cell Death Cascade in the Prefrontal Cortex of Ethanol-Preferring Rats
Neurotoxicity Research (2011)