Antioxidant proteins in fetal brain: superoxide dismutase-1 (SOD-1) protein is not overexpressed in fetal Down syndrome

  • T. Gulesserian
  • E. Engidawork
  • M. Fountoulakis
  • G. Lubec


Exposure of living organisms to reactive oxygen species (ROS), notably oxygen free radicals and hydrogen peroxide is closely linked to the very fact of aerobic life. Oxidants, however, are not always detrimental for cell survival, indeed moderate concentrations of ROS serve as signaling molecules. To maintain this level, cells have evolved an antioxidant defense system. Disruption of this balance leads either to oxidative or reductive stress. Down syndrome (DS) is a genetic disorder associated with oxidative stress. Overexpression of superoxide dismutase-1 (SOD-1) as a result of gene loading is suggested to be responsible for this phenomenon. To examine this view, we investigated the expression of thirteen different proteins involved in the cellular antioxidant defense system in brains of control and DS fetuses by two-dimensional electrophoresis (2-DE) coupled with matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS). No detectable change was found in expression of SOD-1, catalase, phospholipid hydroperoxide glutathione peroxidase, glutathione reductase, antioxidant enzyme AOE372, thioredoxin-like protein and selenium binding protein between control and DS fetuses. By contrast, a significant reduction was observed in levels of glutathione synthetase (P < 0.01), glutathiones-transferase mu2 (P < 0.01), glutathione-S-transferase p (P < 0.05), antioxidant protein 2 (P < 0.05), thioredoxin peroxidase-I (P < 0.05) and thioredoxin peroxidase-II (P < 0.01) in DS compared with controls. The data suggest that oxidative stress in fetal DS does not result from overexpression of SOD-1 protein, rather oxidative stress appears to be the consequence of low levels of reducing agents and enzymes involved in removal of hydrogen peroxide.


Down Syndrome Fetal Brain Antioxidant Protein Gene Dosage Effect Glutathione Synthetase 
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  1. Anneren KG, Epstein CJ (1987) Lipid peroxidation and superoxide dismutase-1 and glutathione peroxidase activities in trisomy 16 fetal mice and human trisomy 21 fibroblast. Pediatr Res 21: 88–92PubMedCrossRefGoogle Scholar
  2. Bae SY, Kang SW, Seo MS, Bainess IC, Tekle E, Chock PB, Rhee SG (1997) Epidermal growth factor (EGF) induced generation of hydrogen peroxide. Role in EGF receptor mediated tyrosine phosphorylation. J Biol Chem 272: 217–221PubMedCrossRefGoogle Scholar
  3. Banks RE, Dunn MJ, Hochstrasser DF, Sanchez JC, Blackstock W, Pappin DJ, Selby PJ (2000) Proteomics: new perspectives, new biomedical opportunities. Lancet 356: 1749–1756PubMedCrossRefGoogle Scholar
  4. Behl C, Davis J, Lesley R, Shubert D (1994) Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77: 817–827PubMedCrossRefGoogle Scholar
  5. Berndt, P, Hobohm U, Langen H (1999) Reliable automatic protein identification from matrix-assisted laser desorption/ionization mass spectrometric peptide fingerprints. Electrophoresis 20: 3521–3526PubMedCrossRefGoogle Scholar
  6. Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254PubMedCrossRefGoogle Scholar
  7. Brooksbank BW, Balazs R (1984) Superoxide dismutase, glutathione peroxidase and lipoperoxidation in Down’s syndrome fetal brain. Brain Res 318: 37–44PubMedGoogle Scholar
  8. Busciglio J, Yankner BA (1995) Apoptosis and increased generation of active oxygen species in Down syndrome neurons in vitro. Nature 378: 776–779PubMedCrossRefGoogle Scholar
  9. Castagne V, Gautschi M, Lefevre K, Posada A, Clarke PGH (1999) Relationships between neuronal death and the cellular redox status. Focus on the developing nervous system. Prog Neurobiol 59: 397–423PubMedCrossRefGoogle Scholar
  10. Chae HZ, Chung SJ, Rhee SG (1994a) Thioredoxin dependent peroxide reductase from yeast. J Biol Chem 269: 27670–27678PubMedGoogle Scholar
  11. Chae HZ, Robinson K, Poole LB, Church G, Storz G, Rhee SG (1994b) Cloning and sequencing of thiol-specific antioxidants from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidants define a large family of antioxidant enzymes. Proc Natl Acad Sci USA 91: 7017–7021PubMedCrossRefGoogle Scholar
  12. Chambers G, Lawrie L, Cash P, Murray GI (2000) Proteomics: a new approach to the study of disease. J Pathol 192: 280–288PubMedCrossRefGoogle Scholar
  13. de Haan JB, Wolvetang EJ, Cristiano F, Iannello R, Bladier C, Keiner MJ, Kola I (1997) Reactive oxygen species and their contribution to pathology in Down syndrome. Adv Pharmacol 38: 379–402PubMedCrossRefGoogle Scholar
  14. Engidawork E, Balic N, Fountoulakis M, Dierssen M, Lubec G (2001) ß-Amyloid precursor protein, ETS-2 and collagen alpha 1 (VI) chain precursor, encoded on chromosome 21, are not overexpressed in fetal Down syndrome: further evidence against gene dosage effect. J Neural Transm (this volume)Google Scholar
  15. Feaster WW, Kwok LW, Epstein CJ (1977) Dosage effects for superoxide dismutase-1 on nucleated cells aneuploid for chromosome 21. Am J Hum Genet 29: 563–570PubMedGoogle Scholar
  16. Fountoulakis M, Langen H (1997) Identification of proteins by matrix assisted laser desorption ionization mass spectrometry following in-gel digestion in low salt, non- volatile buffer and simplified peptide recovery. Anal Biochem 250: 153–156PubMedCrossRefGoogle Scholar
  17. Fridovich I (1978) The biology of oxygen radicals. Science 201: 875–888PubMedCrossRefGoogle Scholar
  18. Gulesserian T, Seidl R, Hardmeier R, Cairns N, Lubec G (2001) Superoxide dismutase SOD1, encoded on chromosome 21, but not SOD2 is overexpressed in brains of patient with Down syndrome. J Invest Med 49: 41–46CrossRefGoogle Scholar
  19. Halliwell B, Gutterridge JMC (1989) Protection against oxidants in biological systems: the superoxide theory of oxygen toxicity. In: Halliwell B, Gutterridge JMC (eds) Free radicals in biology and medicine, 2nd edn. Oxford University Press, New York, pp 86–187Google Scholar
  20. Hayn M, Kresmer K, Singewald N, Cairns N, Nemathova M, Lubec B, Lubec G (1996) Evidence against the involvement of reactive oxygen species in the pathogenesis of neuronal death in Down syndrome and Alzheimer’s disease. Life Sci 59: 537–544PubMedCrossRefGoogle Scholar
  21. Iannello RC, Crack PJ, de Haan JW, Kola I (1999) Oxidative stress and neural dysfunction in Down syndrome. J Neural Transm 57: 257–267Google Scholar
  22. Jakoby WB (1978) The glutathione-S-transferases: a group of multifunctional detoxification proteins. Adv Enzymol Relat Areas Mol Biol 46: 383–314PubMedGoogle Scholar
  23. Jin D, Chae HZ, Rhee SG, Jeang KT (1997) Regulator role for a novel human thioredoxin peroxidase in NFK-B-activation. J Biol Chem 272: 30952–30961PubMedCrossRefGoogle Scholar
  24. Jin LW, Masliah E, Deteresa IR, Mallory M, Sundsmo M, Mori N, Sobel A, Saitoh T (1996) Neurofibrillary tangle associated alteration of stathmin in Alzheimer’s disease. Neurobiol Aging 17: 331–341PubMedCrossRefGoogle Scholar
  25. Kang SW, Bainess IC, Rhee SG (1998a) Characterization of mammalian peroxiredoxin that contain one conserved cysteine. J Biol Chem 273: 6303–6311PubMedCrossRefGoogle Scholar
  26. Kang SW, Chae HZ, Seo MS, Kim K, Bainess IC, Rhee SG (1998a) Mammalian peroxiredoxin isoforms can reduce hydrogen peroxide generated in response to growth factors and tumor necrosis factor-alpha. J Biol Chem 273: 6297–6302PubMedCrossRefGoogle Scholar
  27. Langen H, Röder D, Juranville JF, Fountoulakis M (1997) Effect of the protein application mode and the acrylamide concentration on the resolution of protein spots separated by two-dimensional gel electrophoresis. Electrophoresis 18: 2085–2090PubMedCrossRefGoogle Scholar
  28. Markesbery WR (1999) The role of oxidative stress in Alzheimer’s disease. Arch Neurol 56: 1449–1452PubMedCrossRefGoogle Scholar
  29. Odetti P, Angelini G, Dapino D, Zaccheo D, Garibaldi S, Dagna-Bricarelli F, Piombo G, Perri G, Smith M, Traverso N, Tabaton M (1998) Early glyco-oxidation damage in brains from Down’s syndrome. Biochem Biophys Res Commun 243: 849–851PubMedCrossRefGoogle Scholar
  30. Phelan SA (1999) AOP2 (antioxidant protein 2): structure and function of a unique thiol-specific antioxidant. Antioxd Redox Signal 1: 571–584CrossRefGoogle Scholar
  31. Prospéri M-T, Apiou F, Dutrillaux B, Goubin G (1994) Organizational and chromosomal assignment of two human PAG gene loci: PAGA encoding a functional gene and PAGB a processed pseudogene. Genomics 19: 236–241PubMedCrossRefGoogle Scholar
  32. Seidl R, Greber S, Schuller E, Bernert G, Cairns N, Lubec G (1997) Evidence against increased oxidative DNA damage in Down syndrome brain. Neurosci Lett 235: 137PubMedCrossRefGoogle Scholar
  33. Sen CK, Packer L (1996) Antioxidant and redox regulation of gene expression. FASEB J 10: 709–720PubMedGoogle Scholar
  34. Shau H, Huang ACJ, Faris M, Nazarian R, de Vellis J, Chen W (1998) Thioredoxin peroxidase (natural killer enhancing factor) regulation of activator protein-1 function in endothelial cells. Biochem Biophys Res Commun 249: 683–686PubMedCrossRefGoogle Scholar
  35. Shimbara N, Orino E, Sone S, Ogura T, Takashima M, Shono M, Tamura T, Yasuda H, Tanaka K, Ichihara A (1992) Regulation of gene expression of proteasomes (multiprotease complex) during growth and differentiation of human hematopoietic cells. J Biol Chem 267: 18100–181009PubMedGoogle Scholar
  36. Sies H (1991) Oxidative stress. In: Sies H (ed) Oxidants and antioxidants. Academic Press, London, pp 650Google Scholar
  37. Sies H (1994) Oxidative stress: from basic research to clinical medicine. In: Favier AE, Neve J, Faure P (ed) Trace elements and free radicals in oxidative diseases. AOCS PRESS, Champaign, Illinois, pp 1–7CrossRefGoogle Scholar
  38. Sundaresan M, Yu E-X, Ferrans VJ, Irani K, Finkel T (1995) Requirement for generation of hydrogen peroxide for platelet-derived growth factor signal transduction. Science 270: 296–299PubMedCrossRefGoogle Scholar
  39. Teller JK, Russo C, De Busk LM, Angelini G, Zaccheo D, Dagna-Bricarelli F, Scartezzini P, Bertolini S, Mann DMA, Tabaton M, Gambetti P (1996) Presence of soluble amyloid ß-peptide precedes amyloid plaque formation in Down’s syndrome. Nature Med 2: 93–95PubMedCrossRefGoogle Scholar
  40. Zhang P, Liu B, Kang SW, Seo MS, Rhee SG, Obeid LM (1997) Thioredoxin peroxidase is a novel inhabitor+ of apoptosis with a mechanism distinct from that of Bcl-2. J Biol Chem 272: 30615–30618PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 2001

Authors and Affiliations

  • T. Gulesserian
    • 1
  • E. Engidawork
    • 1
  • M. Fountoulakis
    • 2
  • G. Lubec
    • 1
  1. 1.Department of PediatricsUniversity of ViennaViennaAustria
  2. 2.F. Hoffman-La RocheBaselSwitzerland

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