Oxidative Stress and Mitochondrial Dysfunction in Down Syndrome

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 724)

Abstract

Down syndrome (DS) or trisomy 21 is the genetic disease with highest prevalence displaying phenotypic features that both include neurologic deficiencies and a number of clinical outcomes. DS-associated neurodegeneration recalls the clinical course of Alzheimer disease (AD), due to DS progression toward dementia and amyloid plaques reminiscent of AD clinical course. Moreover, DS represents one of the best documented cases of a human disorder aetiologically related to the redox imbalance that has long been attributed to overexpression of Cu,Zn-superoxide dismutase (SOD-1), encoded by trisomic chromosome 21. The involvement of oxidative stress has been reported both in genes located else than at chromosome 21 and in transcriptional regulation of genes located at other chromosomes. Another well documented hallmark of DS phenotype is represented by a set of immunologic defects encompassing a number of B and T-cell functions and cytokine production, together prompting a proinflammatory state. In turn, this condition can be directly interrelated with an in vivo prooxidant state. As an essential link to oxidative stress, mitochondrial dysfunctions are observed whenever redox imbalances occur, due to the main roles of mitochondria in oxygen metabolism and this is the case for DS. Ultrastructural and biochemical abnormalities were reported in mitochondria from human DS patients and from trisomy 16 (Ts16) mice, to be reviewed in this chapter. Together, in vivo alterations of mitochondrial function are consistent with a prooxidant state as a phenotypic hallmark in DS.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hayes A, Batshaw ML. Down syndrome. Pediatr Clin North Am 1993; 40:523–535.PubMedGoogle Scholar
  2. 2.
    Musiani P, Valitutti S, Castellino F et al. Intrathymic deficient expansion of T-cell precursors in Down syndrome. Am J Med Genet Suppl 1990; 7:219–224.PubMedGoogle Scholar
  3. 3.
    Hasle H. Pattern of malignant disorders in individuals with Down’s syndrome. Lancet Oncol 2001; 2:429–436.PubMedCrossRefGoogle Scholar
  4. 4.
    Lott IT, Head E. Down syndrome and Alzheimer’s disease: a link between development and aging. Ment Retard Dev Disabil Res Rev 2001; 7:172–178.PubMedCrossRefGoogle Scholar
  5. 5.
    Brooksbank BW, Balasz R. Superoxide dismutase, glutathione peroxidase and lipoperoxidation in Down’s syndrome fetal brain. Exp Brain Res 1984; 16:37–44.Google Scholar
  6. 6.
    Kedziora J, Bartosz G. Down’s syndrome: A pathology involving the lack of balance of reactive oxygen species. Free Rad Biol Med 1988; 4:317–330.PubMedCrossRefGoogle Scholar
  7. 7.
    Groner Y, Elroy-Stein O, Avraham KB et al. Cell damage by excess CuZnSOD and Down’s syndrome. Biomed Pharmacother 1994; 48:231–240.PubMedCrossRefGoogle Scholar
  8. 8.
    Busciglio J, Yankner BA. Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature 1995; 378:776–779.PubMedCrossRefGoogle Scholar
  9. 9.
    Balcz B, Kirchner L, Cairns N et al. Increased brain protein levels of carbonyl reductase and alcohol dehydrogenase in Down syndrome and Alzheimer’s disease. J Neural Transm Suppl 2001; 61:193–201.PubMedGoogle Scholar
  10. 10.
    Epstein CJ, Avraham KB, Lovett M et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: Animal model of dosage effects in Down syndrome. Proc Natl Acad Sci USA 1987; 84:8044–8048.PubMedCrossRefGoogle Scholar
  11. 12.
    Muchová J, Sustrová M, Garaiová I et al. Influence of age on activities of antioxidant enzymes and lipid peroxidation products in erythrocytes and neutrophils of Down syndrome patients. Free Radic Biol Med 2001; 31:499–508.PubMedCrossRefGoogle Scholar
  12. 13.
    Garaiová I, Muchová J, Šustrová M et al. The relationship between antioxidant systems and some markers of oxidative stress in persons with Down syndrome. Biologia (Bratislava) 2004; 59:781–788.Google Scholar
  13. 14.
    Slonim DK, Koide K, Johnson KL et al. Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses. Proc Natl Acad Sci USA 2009; 106:9425–9429.PubMedCrossRefGoogle Scholar
  14. 15.
    Conti A, Fabbrini F, D’Agostino P et al. Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy. BMC Genomics 2007; 8:268.PubMedCrossRefGoogle Scholar
  15. 14.
    Pastor MC, Sierra C, Dolade M et al. Antioxidant enzymes and fatty acid status in erythrocytes of Down’s syndrome patients. Clin Chem 1998; 44:924–929.PubMedGoogle Scholar
  16. 15.
    Garcez ME, Peres W, Salvador M. Oxidative stress and hematologic and biochemical parameters in individuals with Down syndrome. Mayo Clin Proc 2005; 80:1607–1611.PubMedCrossRefGoogle Scholar
  17. 16.
    Casado A, López-Fernández ME, Ruíz R. Lipid peroxidation in Down syndrome caused by regular trisomy 21, trisomy 21 by Robertsonian translocation and mosaic trisomy 21. Clin Chem Lab Med 2007; 45:59–62.PubMedCrossRefGoogle Scholar
  18. 17.
    Pallardó FV, Degan P, d’Ischia M et al. Higher age-related prooxidant state in young Down syndrome patients indicates accelerated aging. Biogerontology 2006; 7:211–220.PubMedCrossRefGoogle Scholar
  19. 18.
    Zana M, Szécsényi A, Czibula A et al. Age-dependent oxidative stress-induced DNA damage in Down’s lymphocytes. Biochem Biophys Res Commun. 2006; 345:726–733.PubMedCrossRefGoogle Scholar
  20. 19.
    Žitňanová I, Korytar P, Aruoma OI et al. Uric acid and allantoin levels in Down syndrome: antioxidant and oxidative stress mechanisms. Clin Chim Acta 2004; 341:139–146.PubMedCrossRefGoogle Scholar
  21. 20.
    Uberos J, Romero J, Molina-Carballo A et al. Melatonin and elimination of kynurenines in children with Down’s syndrome. J Pediatr Endocrinol Metab 2010; 23:277–282.PubMedCrossRefGoogle Scholar
  22. 21.
    Coppus AM, Fekkes D, Verhoeven WM et al. Plasma levels of nitric oxide related amino acids in demented subjects with Down syndrome are related to neopterin concentrations. Amino Acids 2010; 38:923–928.PubMedCrossRefGoogle Scholar
  23. 22.
    Nagyová A, Sustrová M, Raslová K. Serum lipid resistance to oxidation and uric acid levels in subjects with Down’s syndrome. Physiol Res 2000; 49:227–231.PubMedGoogle Scholar
  24. 23.
    Jovanovic SV, Clements D, MacLeod K. Biomarkers of oxidative stress are significantly elevated in Down syndrome. Free Radic Biol Med 1998; 25:1044–1048.PubMedCrossRefGoogle Scholar
  25. 24.
    Pratico D, Iuliano L, Amerio G et al. Down’s syndrome is associated with increased 8,12-iso-iPF2alpha-VI levels: evidence for enhanced lipid peroxidation in vivo. Ann Neurol 2000; 48:795–798.PubMedCrossRefGoogle Scholar
  26. 25.
    Perrone S, Longini M, Bellieni CV et al. Early oxidative stress in amniotic fluid of pregnancies with Down syndrome. Clin Biochem 2007; 40:177–180.PubMedCrossRefGoogle Scholar
  27. 26.
    Miller ME, Mellman Cohen MM, Kohn G et al. Depressed immunoglobulin G in newborn infants with Down’s syndrome. J Pediatr 1969; 75:996–1000.PubMedCrossRefGoogle Scholar
  28. 27.
    Lopez V. Serum IgE concentration in trisomy 21. J Ment Defic Res 1974; 18:111–114.PubMedGoogle Scholar
  29. 28.
    Burgio GR, Lanzavecchia A, Maccario R et al. Immunodeficiency in Down’s syndrome: T-lymphocyte subset imbalance in trisomic children. Clin Exp Immunol 1978; 33:298–301.PubMedGoogle Scholar
  30. 29.
    Mrak RE, Griffin WS. Trisomy 21 and the brain. J Neuropathol Exp Neurol. 2004; 63:679–685.PubMedGoogle Scholar
  31. 30.
    Griffin WS. Inflammation and neurodegenerative diseases. Am J Clin Nutr 2006; 83:470S–474S.PubMedGoogle Scholar
  32. 31.
    Shimada A, Hayashi Y, Ogasawara M et al. Pro-inflammatory cytokinemia is frequently found in Down syndrome patients with hematological disorders. Leuk Res 2007; 31:1199–1203.PubMedCrossRefGoogle Scholar
  33. 32.
    Guazzarotti L, Trabattoni D, Castelletti E et al. T-lymphocyte maturation is impaired in healthy young individuals carrying trisomy 21 (Down syndrome). Am J Intellect Dev Disabil 2009; 114:100–109.PubMedCrossRefGoogle Scholar
  34. 33.
    Cetiner S, Demirhan O, Inal TC et al. Analysis of peripheral blood T-cell subsets, natural killer cells and serum levels of cytokines in children with Down syndrome. Int J Immunogenet 2010; 37:233–237.PubMedCrossRefGoogle Scholar
  35. 34.
    Bloemers BL, van Bleek GM, Kimpen JL et al. Distinct abnormalities in the innate immune system of children with Down syndrome. J Pediatr 2010; 156:804–809.PubMedCrossRefGoogle Scholar
  36. 35.
    Costa V, Sommese L, Casamassimi A et al. Impairment of circulating endothelial progenitors in Down syndrome. BMC Med Genomics 2010; 3:40.PubMedCrossRefGoogle Scholar
  37. 36.
    Roberts RA, Smith RA, Safe S et al. Toxicological and pathophysiological roles of reactive oxygen and nitrogen species. Toxicology 2010; 276:85–94.PubMedCrossRefGoogle Scholar
  38. 37.
    Candore G, Bulati M, Caruso C et al. Inflammation, cytokines, immune response, apolipoprotein E, cholesterol and oxidative stress in Alzheimer disease: therapeutic implications. Rejuvenation Res 2010; 13:301–313.PubMedCrossRefGoogle Scholar
  39. 38.
    Galasko D, Montine TJ. Biomarkers of oxidative damage and inflammation in Alzheimer’s disease. Biomark Med 2010; 4:27–36.PubMedCrossRefGoogle Scholar
  40. 39.
    Prince J, Jia S, Båve U et al. Mitochondrial enzyme deficiencies in Down’s syndrome. J Neural Transm Park Dis Dement Sect 1994; 8:171–181.PubMedCrossRefGoogle Scholar
  41. 40.
    Bersu ET, Ahmad FJ, Schwei MJ et al. Cytoplasmic abnormalities in cultured cerebellar neurons from the trisomy 16 mouse. Brain Res Dev Brain Res 1998; 109:115–120.PubMedCrossRefGoogle Scholar
  42. 41.
    Schuchmann S, Heinemann U. Increased mitochondrial superoxide generation in neurons from trisomy 16 mice: a model of Down’s syndrome. Free Radic Biol Med 2000; 28:235–250.PubMedCrossRefGoogle Scholar
  43. 42.
    Capone G, Kim P, Jovanovich S et al. Evidence for increased mitochondrial superoxide production in Down syndrome. Life Sci 2002; 70:2885–2895.PubMedCrossRefGoogle Scholar
  44. 43.
    Bambrick LL, Fiskum G. Mitochondrial dysfunction in mouse trisomy 16 brain. Brain Res 2008; 1188:9–16.PubMedCrossRefGoogle Scholar
  45. 44.
    Busciglio J, Pelsman A, Wong C et al. Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down’s syndrome. Neuron 2002; 33:677–688.PubMedCrossRefGoogle Scholar
  46. 45.
    Druzhyna N, Nair RG, LeDoux SP et al. Defective repair of oxidative damage in mitochondrial DNA in Down’s syndrome. Mutat Res 1998; 409:81–89.PubMedGoogle Scholar
  47. 46.
    Conti A, Fabbrini F, D’Agostino P et al. Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy. BMC Genomics 2007; 8:268.PubMedCrossRefGoogle Scholar
  48. 47.
    Roat E, Prada N, Ferraresi R et al. Mitochondrial alterations and tendency to apoptosis in peripheral blood cells from children with Down syndrome. FEBS Lett 2007; 581:521–525.PubMedCrossRefGoogle Scholar
  49. 48.
    Pallardó FV, Lloret A, Lebel M et al. Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-T elangiectasia, Down syndrome, Fanconi Anaemia and Werner syndrome. Biogerontology 2010; 11:401–419.PubMedCrossRefGoogle Scholar
  50. 49.
    Harman D. Alzheimer’s disease pathogenesis: role of aging. Ann NY Acad Sci 2006; 1067:454–460.PubMedCrossRefGoogle Scholar
  51. 50.
    Ristow M. Neurodegenerative disorders associated with diabetes mellitus. J Mol Med 2004; 82:510–529.PubMedCrossRefGoogle Scholar
  52. 51.
    McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutrition 1935; 10:63–79.Google Scholar
  53. 52.
    Csiszar A, Labinskyy N, Podlutsky A et al. Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. Am J Physiol Heart Circ Physiol 2008; 294:H2721–H2735.PubMedCrossRefGoogle Scholar
  54. 53.
    Baur JA, Pearson KJ, Price NL et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444:337–342.PubMedCrossRefGoogle Scholar
  55. 54.
    Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res 2008; 33:194–203.PubMedCrossRefGoogle Scholar
  56. 55.
    Palaniappan AR, Dai A. Mitochondrial ageing and the beneficial role of alpha-lipoic acid. Neurochem Res 2007; 32:1552–1558.PubMedCrossRefGoogle Scholar
  57. 56.
    Plecitá-Hlavatá L, Jezek J, Jezek P. Pro-oxidant mitochondrial matrix-targeted ubiquinone MitoQ10 acts as anti-oxidant at retarded electron transport or proton pumping within Complex I. Int J Biochem Cell Biol 2009; 41:1697–1707.PubMedCrossRefGoogle Scholar
  58. 57.
    Long J, Wang X, Gao H et al. D-galactose toxicity in mice is associated with mitochondrial dysfunction: protecting effects of mitochondrial nutrient R-alpha-lipoic acid. Biogerontology 2007; 8:373–381.PubMedCrossRefGoogle Scholar
  59. 58.
    Gadaleta MN, Petruzzella V, Renis M et al. Reduced transcription of mitochondrial DNA in the senescent rat. Tissue dependence and effect of l-carnitine. Eur J Biochem 1990; 187:501–506.PubMedCrossRefGoogle Scholar
  60. 59.
    Traina G, Federighi G, Brunelli M et al. Cytoprotective effect of acetyl-l-carnitine evidenced by analysis of gene expression in the rat brain. Mol Neurobiol 2009; 39:101–106.PubMedCrossRefGoogle Scholar
  61. 60.
    Madiraju P, Pande SV, Prentki M et al. Mitochondrial acetylcarnitine provides acetyl groups for nuclear histone acetylation. Epigenetics 2009; 4:399–403.PubMedCrossRefGoogle Scholar
  62. 61.
    Rosca MG, Lemieux H, Hoppel CL. Mitochondria in the elderly: is acetylcarnitine a rejuvenator. Adv Drug Deliv Rev 2009; 61:1332–1342.PubMedCrossRefGoogle Scholar
  63. 62.
    Rodriguez MC, Macdonald JR, Mahoney DJ et al. Beneficial effects of creatine, CoQ10 and lipoic acid in mitochondrial disorders. Muscle Nerve 2007; 35:235–242.PubMedCrossRefGoogle Scholar
  64. 63.
    Savitha S, Panneerselvam C. Mitigation of age-dependent oxidative damage to DNA in rat heart by carnitine and lipoic acid. Mech Ageing Dev 2007; 128:206–212.PubMedCrossRefGoogle Scholar
  65. 64.
    Maroz A, Anderson RF, Smith RAJ et al. Reactivity of ubiquinone and ubiquinol with superoxide and the hydroperoxyl radical: implications for in vivo antioxidant activity. Free Radic Biol Med 2009; 46:105–109.PubMedCrossRefGoogle Scholar
  66. 65.
    Miles MV, Patterson BJ, Chalfonte-Evans ML et al. Coenzyme Q10 (ubiquinol-10) supplementation improves oxidative imbalance in children with trisomy 21. Pediatr Neurol 2007; 37:398–403.PubMedCrossRefGoogle Scholar
  67. 66.
    Tiano L, Carnevali P, Padella L et al. Effect of Coenzyme Q(10) in mitigating oxidative DNA damage in Down syndrome patients, a double blind randomized controlled trial. Neurobiol Aging 2009; doi:10.1016/j. neurobiolaging.2009.11.016.Google Scholar
  68. 67.
    Kaufmann P, Thompson JL, Levy G et al. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol 2009; 66:235–244.PubMedCrossRefGoogle Scholar
  69. 68.
    Storch A, Jost WH, Vieregge P et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol 2007; 64:938–944.PubMedCrossRefGoogle Scholar
  70. 69.
    Caso G, Kelly P, McNurlan MA et al. Effect of coenzyme Q10 on myopathic symptoms in patients treated with statins. Am J Cardiol 2007; 99:1409–1412.PubMedCrossRefGoogle Scholar
  71. 70.
    Palacká P, Kucharská J, Murin J et al. Complementary therapy in diabetic patients with chronic complications: a pilot study. Bratisl Lek Listy 2010; 111:205–211.PubMedGoogle Scholar
  72. 71.
    Hertz N, Lister RE. Improved survival in patients with end-stage cancer treated with coenzyme Q(10) and other antioxidants: a pilot study. J Int Med Res 2009; 37:1961–1971.PubMedGoogle Scholar
  73. 72.
    Tarnopolsky MA. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv Drug Deliv Rev 2008; 60:1561–1567.PubMedCrossRefGoogle Scholar
  74. 73.
    Vila M, Ramonet D, Perier C. Mitochondrial alterations in Parkinson’s disease: new clues. J Neurochem 2008; 107:317–328.PubMedCrossRefGoogle Scholar
  75. 74.
    Wang X, Su B, Lee HG et al. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 2009; 28:9090–9103.CrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  1. 1.CROMCancer Research CenterMercoglianoItaly

Personalised recommendations