Genome-wide gene deregulation and oxidative stress appear to be critical factors determining the high variability of phenotypes in Down’s syndrome (DS). Even though individuals with trisomy 21 exhibit a higher survival rate compared to other aneuploidies, most of them die in utero or early during postnatal life. While the survivors are currently predicted to live past 60 years, they suffer higher incidence of age-related conditions including Alzheimer’s disease (AD). This paper is centered on the mechanisms by which mitochondrial factors and oxidative stress may orchestrate an adaptive response directed to maintain basic cellular functions and survival in DS. In this context, the timing of therapeutic interventions should be carefully considered for the successful treatment of chronic disorders in the DS population. 1. Introduction Down’s syndrome (DS) or trisomy 21 is a prevalent genetic cause of intellectual disability due to full or partial triplication of chromosome 21 (HSA21). The presentation varies greatly between individuals. The molecular bases of this variation is “the gene dosage effect” caused by the extra chromosome 21, which leads to a global imbalance on gene expression [1]. However, the molecular mechanisms by which such gene dosage imbalance causes DS-specific abnormalities remain unclear. Albeit trisomy 21 is the most common aneuploidy that infants can survive, the rate of miscarriage of fetuses with DS during the first trimester is almost 50% [2]. The survival rate for the first 18 years of life of DS individuals is 50.3% of the total DS population, and the greatest percent of deaths is observed during the first 5 years of life (35.9%). The death rate drops to 13.1% between 19 and 40 years, and DS individuals of 40+ years have a greater chance to live beyond 60 years of age in developed countries, especially those without congenital heart disease [3]. A remarkable feature of the syndrome is the presence of Alzheimer’s disease (AD) neuropathology in the brain of nearly all DS individuals, the majority of which develop dementia with age [4]. Besides dementia, other aging features appear prematurely such as cataracts, diabetes, hair graying, leukemia, and hearing and visual impairment. Together, they define DS as a “segmental progeroid syndrome” [5–7]. Mitochondria represent both a principal source as well as a target of free radicals, which in turn cause structural damage and activate signaling pathways associated with ageing and age-related diseases [8–10]. Both oxidative stress and mitochondrial dysfunction are prominent features of
References
[1]
M. A. Pritchard and I. Kola, “The “gene dosage effect” hypothesis versus the “amplified developmental instability” hypothesis in Down syndrome,” Journal of Neural Transmission, Supplement, no. 57, pp. 293–303, 1999.
[2]
N. Leporrier, M. Herrou, R. Morello, and P. Leymarie, “Fetuses with Down's syndrome detected by prenatal screening are more likely to abort spontaneously than fetuses with Down's syndrome not detected by prenatal screening,” Journal of Obstetrics and Gynaecology, vol. 110, no. 1, pp. 18–21, 2003.
[3]
A. H. Bittles, C. Bower, R. Hussain, and E. J. Glasson, “The four ages of Down syndrome,” European Journal of Public Health, vol. 17, no. 2, pp. 221–225, 2007.
[4]
A. Coppus, H. Evenhuis, G. J. Verberne et al., “Dementia and mortality in persons with Down's syndrome,” Journal of Intellectual Disability Research, vol. 50, no. 10, pp. 768–777, 2006.
[5]
G. M. Martin, “Genetic syndromes in man with potential relevance to the pathobiology of aging,” Birth Defects, vol. 14, no. 1, pp. 5–39, 1978.
[6]
L. Colvin, S. B. Jurenka, and M. I. Van Allen, Down Syndrome, Marcel Dekker, New York, NY, USA, 2003.
[7]
F. V. Pallardó, A. Lloret, M. Lebel et al., “Mitochondrial dysfunction in some oxidative stress-related genetic diseases: ataxia-telangiectasia, Down syndrome, fanconi anaemia and werner syndrome,” Biogerontology, vol. 11, no. 4, pp. 401–419, 2010.
[8]
D. Harman, “Free radical theory of aging: dietary implications,” American Journal of Clinical Nutrition, vol. 25, no. 8, pp. 839–843, 1972.
[9]
D. Harman, “The biologic clock: the mitochondria?” Journal of the American Geriatrics Society, vol. 20, no. 4, pp. 145–147, 1972.
[10]
J. Miquel and J. E. Fleming, “A two-step hypothesis on the mechanisms of in vitro cell aging: cell differentiation followed by intrinsic mitochondrial mutagenesis,” Experimental Gerontology, vol. 19, no. 1, pp. 31–36, 1984.
[11]
G. Cenini, A. L. Dowling, T. L. Beckett et al., “Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome,” Biochimica et Biophysica Acta, vol. 1822, no. 2, pp. 130–138, 2012.
[12]
M. Perluigi and D. A. Butterfield, “The identification of protein biomarkers for oxidative stress in Down syndrome,” Expert Review of Proteomics, vol. 8, no. 4, pp. 427–429, 2011.
[13]
J. Busciglio, A. Pelsman, C. Wong et al., “Altered metabolism of the amyloid β precursor protein is associated with mitochondrial dysfunction in Down's syndrome,” Neuron, vol. 33, no. 5, pp. 677–688, 2002.
[14]
E. A. Shukkur, A. Shimohata, T. Akagi et al., “Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome,” Human Molecular Genetics, vol. 15, no. 18, pp. 2752–2762, 2006.
[15]
I. T. Lott, E. Head, E. Doran, and J. Busciglio, “Beta-amyloid, oxidative stress and down syndrome,” Current Alzheimer Research, vol. 3, no. 5, pp. 521–528, 2006.
[16]
L. Tiano and J. Busciglio, “Mitochondrial dysfunction and Down's syndrome: is there a role for CoQ10?” BioFactors, vol. 37, no. 5, pp. 386–392, 2011.
[17]
S. Porta, S. A. Serra, M. Huch et al., “RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: apotential pathogenic process in neurodegeneration,” Human Molecular Genetics, vol. 16, no. 9, pp. 1039–1050, 2007.
[18]
D. C. Wallace, “A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine,” Annual Review of Genetics, vol. 39, pp. 359–407, 2005.
[19]
D. C. Wallace and W. Fan, “Energetics, epigenetics, mitochondrial genetics,” Mitochondrion, vol. 10, no. 1, pp. 12–31, 2010.
[20]
B. Sjodin, Y. Hellsten Westing, and F. S. Apple, “Biochemical mechanisms for oxygen free radical formation during exercise,” Sports Medicine, vol. 10, no. 4, pp. 236–254, 1990.
[21]
D. C. Wallace, “Why do we still have a maternally inherited mitochondrial DNA? insights from evolutionary medicine,” Annual Review of Biochemistry, vol. 76, pp. 781–821, 2007.
[22]
P. Helguera, A. Pelsman, G. Pigino, E. Wolvetang, E. Head, and J. Busciglio, “ets-2 promotes the activation of a mitochondrial death pathway in down's syndrome neurons,” Journal of Neuroscience, vol. 25, no. 9, pp. 2295–2303, 2005.
[23]
E. A. Schon, S. H. Kim, J. C. Ferreira et al., “Chromosomal non-disjunction in human oocytes: is there a mitochondrial connection?” Human Reproduction, vol. 15, no. 2, pp. 160–172, 2000.
[24]
Y. Koga, Y. Akita, N. Takane, Y. Sato, and H. Kato, “Heterogeneous presentation in A3243G mutation in the mitochondrial tRNALeu(UUR) gene,” Archives of Disease in Childhood, vol. 82, no. 5, pp. 407–411, 2000.
[25]
S. Arbuzova, H. Cuckle, R. Mueller, and I. Sehmi, “Familial down syndrome: evidence supporting cytoplasmic inheritance,” Clinical Genetics, vol. 60, no. 6, pp. 456–462, 2001.
[26]
S. Arbuzova, T. Hutchin, and H. Cuckle, “Mitochondrial dysfunction and Down's syndrome,” BioEssays, vol. 24, no. 8, pp. 681–684, 2002.
[27]
U. Eichenlaub-Ritter, M. Wieczorek, S. Lüke, and T. Seidel, “Age related changes in mitochondrial function and new approaches to study redox regulation in mammalian oocytes in response to age or maturation conditions,” Mitochondrion, vol. 11, pp. 783–796, 2011.
[28]
U. Eichenlaub-Ritter, “Reproductive semi-cloning respecting biparental origin. Reconstitution of gametes for assisted reproduction,” Human Reproduction, vol. 18, no. 3, pp. 473–475, 2003.
[29]
P. E. Coskun, J. Wyrembak, O. Derbereva et al., “Systemic mitochondrial dysfunction and the etiology of Alzheimer's disease and down syndrome dementia,” Journal of Alzheimer's Disease, vol. 20, supplement 2, pp. S293–S310, 2010.
[30]
P. E. Coskun, M. F. Beal, and D. C. Wallace, “Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 29, pp. 10726–10731, 2004.
[31]
N. Druzhyna, R. G. Nair, S. P. Ledoux, and G. L. Wilson, “Defective repair of oxidative damage in mitochondrial DNA in Down's syndrome,” Mutation Research, vol. 409, no. 2, pp. 81–89, 1998.
[32]
Z. Nagy, M. M. Esiri, M. LeGris, and P. M. Matthews, “Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology,” Acta Neuropathologica, vol. 97, no. 4, pp. 346–354, 1999.
[33]
S. H. Kim, R. Vlkolinsky, N. Cairns, M. Fountoulakis, and G. Lubec, “The reduction of NADH—ubiquinone oxidoreductase 24- and 75-kDa subunits in brains of patients with Down syndrome and Alzheimer's disease,” Life Sciences, vol. 68, no. 24, pp. 2741–2750, 2001.
[34]
S. H. Lee, S. Lee, H. S. Jun et al., “Expression of the mitochondrial ATPase6 gene and Tfam in down syndrome,” Molecules and Cells, vol. 15, no. 2, pp. 181–185, 2003.
[35]
D. Valenti, G. A. Manente, L. Moro, E. Marra, and R. A. Vacca, “Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway,” Biochemical Journal, vol. 435, no. 3, pp. 679–688, 2011.
[36]
P. Bozner, G. L. Wilson, N. M. Druzhyna et al., “Deficiency of chaperonin 60 in Down's syndrome,” Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 479–486, 2002.
[37]
J. Martin, A. L. Horwich, and F. U. Hartl, “Prevention of protein denaturation under heat stress by the chaperonin Hsp60,” Science, vol. 258, no. 5084, pp. 995–998, 1992.
[38]
M. Bajo, J. Fruehauf, S. H. Kim, M. Fountoulakis, and G. Lubec, “Proteomic evaluation of intermediary metabolism enzyme proteins in fetal down's syndrome cerebral cortex,” Proteomics, vol. 2, no. 11, pp. 1539–1546, 2002.
[39]
J. H. Shin, R. Weitzdoerfer, M. Fountoulakis, and G. Lubec, “Expression of cystathionine β-synthase, pyridoxal kinase, and ES1 protein homolog (mitochondrial precursor) in fetal Down syndrome brain,” Neurochemistry International, vol. 45, no. 1, pp. 73–79, 2004.
[40]
K. R. Martin and J. C. Barrett, “Reactive oxygen species as double-edged swords in cellular processes: low-dose cell signaling versus high-dose toxicity,” Human and Experimental Toxicology, vol. 21, no. 2, pp. 71–75, 2002.
[41]
M. Birringer, “Hormetics: dietary triggers of an adaptive stress response,” Pharmaceutical Research, vol. 28, no. 11, pp. 2680–2694, 2011.
[42]
E. J. Calabrese and L. A. Baldwin, “Defining hormesis,” Human and Experimental Toxicology, vol. 21, no. 2, pp. 91–97, 2002.
[43]
S. E. Schriner, N. J. Linford, G. M. Martin et al., “Medecine: extension of murine life span by overexpression of catalase targeted to mitochondria,” Science, vol. 308, no. 5730, pp. 1909–1911, 2005.
[44]
L. A. Harrington and C. B. Harley, “Effect of vitamin E on lifespan and reproduction in Caenorhabditis elegans,” Mechanisms of Ageing and Development, vol. 43, no. 1, pp. 71–78, 1988.
[45]
W. C. Orr and R. S. Sohal, “Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster,” Science, vol. 263, no. 5150, pp. 1128–1130, 1994.
[46]
S. Melov, J. Ravenscroft, S. Malik et al., “Extension of life-span with superoxide dismutase/catalase mimetics,” Science, vol. 289, no. 5484, pp. 1567–1569, 2000.
[47]
I. T. Lott, E. Doran, V. Q. Nguyen, A. Tournay, E. Head, and D. L. Gillen, “Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation,” American Journal of Medical Genetics A, vol. 155, no. 8, pp. 1939–1948, 2011.
[48]
J. Lapointe and S. Hekimi, “When a theory of aging ages badly,” Cellular and Molecular Life Sciences, vol. 67, no. 1, pp. 1–8, 2010.
[49]
M. Ristow and S. Schmeisser, “Extending life span by increasing oxidative stress,” Free Radical Biology and Medicine, vol. 51, no. 2, pp. 327–336, 2011.
[50]
I. T. Lott, “Antioxidants in Down syndrome,” Biochim Biophys Acta, vol. 1822, no. 5, pp. 657–663, 2012.
[51]
E. J. Masoro and S. N. Austad, “The evolution of the antiaging action of dietary restriction: a hypothesis,” Journals of Gerontology A, vol. 51, no. 6, pp. B387–B391, 1996.
[52]
P. K. Sharma, V. Agrawal, and N. Roy, “Mitochondria-mediated hormetic response in life span extension of calorie-restricted Saccharomyces cerevisiae,” Age, vol. 33, no. 2, pp. 143–154, 2011.
[53]
M. McMahon, N. Thomas, K. Itoh, M. Yamamoto, and J. D. Hayes, “Dimerization of substrate adaptors can facilitate Cullin-mediated ubiquitylation of proteins by a “tethering” mechanism: a two-site interaction model for the Nrf2-Keap1 complex,” Journal of Biological Chemistry, vol. 281, no. 34, pp. 24756–24768, 2006.
[54]
K. Itoh, J. Mimura, and M. Yamamoto, “Discovery of the negative regulator of Nrf2, keap1: a historical overview,” Antioxidants and Redox Signaling, vol. 13, no. 11, pp. 1665–1678, 2010.
[55]
A. N. Kong, E. Owuor, R. Yu et al., “Induction of xenobiotic enzymes by the map kinase pathway and the antioxidant or electrophile response element (ARE/EpRE),” Drug Metabolism Reviews, vol. 33, no. 3-4, pp. 255–271, 2001.
[56]
P. Helguera, J. Seiglie, J. Rodriguez, and J. Busciglio, “Adaptive downregulation of mitochondrial function in Down’s syndrome,” submitted.
[57]
J. E. Swatton, L. A. Sellers, R. L. Faull, A. Holland, S. Iritani, and S. Bahn, “Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain,” European Journal of Neuroscience, vol. 19, no. 10, pp. 2711–2719, 2004.
[58]
K. Taguchi, H. Motohashi, and M. Yamamoto, “Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution,” Genes to Cells, vol. 16, no. 2, pp. 123–140, 2011.
[59]
H. Zhu, K. Itoh, M. Yamamoto, J. L. Zweier, and Y. Li, “Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: protection against reactive oxygen and nitrogen species-induced cell injury,” FEBS Letters, vol. 579, no. 14, pp. 3029–3036, 2005.
[60]
A. Strydom, M. J. Dickinson, S. Shende, D. Pratico, and Z. Walker, “Oxidative stress and cognitive ability in adults with Down syndrome,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 33, no. 1, pp. 76–80, 2009.
[61]
X. Wang and C. X. Hai, “ROS acts as a double-edged sword in the pathogenesis of Type 2 diabetes mellitus: is Nrf2 a potential target for the treatment?” Mini-Reviews in Medicinal Chemistry, vol. 11, no. 12, pp. 1082–1092, 2011.
[62]
M. Ristow, K. Zarse, A. Oberbach et al., “Antioxidants prevent health-promoting effects of physical exercise in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 21, pp. 8665–8670, 2009.
