Skip to main content
SpringerLink
Log in
Book cover

Handbook of Neurochemistry and Molecular Neurobiology pp 345–358Cite as

Gene Hunting by Substractive Hybridization in Down Syndrome Correlation with Proteomics Analysis

  • Reference work entry
  • First Online:

Abstract:

Down syndrome (DS) or trisomy 21 is a complex genetic and metabolic disorder and the most common genetic cause of mental retardation with an incidence of 1 in about 700 live births. DS is associated with facial dysmorphology, congenital heart defects, high accidence of acute megakaryoblastic leukemias in childhood, immunologic disorders, thyroid dysfunction, frequent diabetes mellitus, etc. Around the third decade of life patients with DS usually develop neuropathological features of Alzheimer's disease (AD).

For a long time, “gene dosage effect” was believed to underlie the abnormalities characteristic for DS; recent studies, however, have shown this theory to be too simplistic. In spite of plenty of projects devoted to DS, molecular pathomechanisms leading to singular DS complications remain quite unclear. Research in this field has accelerated in recent years, applying highly sensitive molecular biology instruments and technologies. Thereby, subtractive hybridization (SH) and brain proteomics (BP) belong to the group of most effective tools developed for the identification of disease‐specific gene expression—so‐called “disease proteome/transcriptome.”

Here we report an overview about SH and BP results achieved through ex vivo comparative analysis of human fetal DS brains versus controls. The functional alterations found are stretched on the whole complex of cellular events in DS regarding brain development, cell reproduction, DNA replication, quality control and repair, synthesis of gene products, stress response, antitumor controlling mechanisms, central metabolic processes like metabolism of glucose and amino acids, function of single subcellular structures such as mitochondria, energy metabolism, neutralization of reactive oxygen species, general brain detoxification, and complex neuronal function. Affected molecular pathways demonstrate a clear predisposition of DS for neurodegeneration, cancer, and AD. Gene expression alterations overlapping between DS and AD pathomechanisms might be further considered as potential molecular markers for early diagnosis of AD predisposition also in non‐DS individuals.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   249.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

AD:

Alzheimer’s Disease

CNS:

Central Nervous System

DS:

Down Syndrome

GABA:

Gamma‐Amino‐Butyric Acid

SH:

Subtractive Hybridization

References

  • Azmitia EC. 2001. Neuronal instability: implications for Rett's syndrome. Brain Dev 23: S1–S10.

    Article  PubMed  Google Scholar 

  • Branconnier RJ, Branconnier ME, Walshe TM, McCarthy C, Morse PA. 1992. Blocking the Ca(2+)-activated cytotoxic mechanisms of cholinergic neuronal death: A novel treatment strategy for Alzheimer's disease. Psychopharmacol Bull 28: 175–181.

    CAS  PubMed  Google Scholar 

  • Busciglio J, Yankner BA. 1995. Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro. Nature 378: 776–779.

    Article  CAS  PubMed  Google Scholar 

  • Capone G, Kim P, Jovanovich S, Payne L, Freund L, et al. 2002. Evidence for increased mitochondrial superoxide production in Down syndrome. Life Sci 70: 2885–2895.

    Article  CAS  PubMed  Google Scholar 

  • Chadefaux B, Rethore MO, Raoul O, Ceballos I, Poissonnier M, et al. 1985. Cystathionine beta synthase: Gene dosage effect in trisomy 21. Biochem Biophys Res Commun 128: 40–44.

    Article  CAS  PubMed  Google Scholar 

  • Chadefaux B, Ceballos I, Hamet M, Coude M, Poissonnier M, et al. 1988. Is absence of atheroma in Down syndrome due to decreased homocysteine levels? Lancet 2: 741.

    Article  CAS  PubMed  Google Scholar 

  • Crews FT, Kurian P, Freund G. 1994. Cholinergic and serotonergic stimulation of phosphoinositide hydrolysis is decreased in Alzheimer's disease. Life Sci 55: 1993–2002.

    Article  CAS  PubMed  Google Scholar 

  • Diedrich JF, Minnigan H, Carp RI, Whitaker JN, Race R, et al. 1991. Neuropathological changes in scrapie and Alzheimer's disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes. J Virol 65: 4759–4768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang-Kircher SG, Labudova O, Kitzmueller E, Rink H, Cairns N, et al. 1999. Increased steady state mRNA levels of DNA-repair genes XRCC1, ERCC2 and ERCC3 in brain of patients with Down syndrome. Life Sci 64: 1689–1699.

    Article  CAS  PubMed  Google Scholar 

  • Fountoulakis M. 2001. Proteomics: Current technologies and applications in neurological disorders and toxicology. Amino Acids 21: 363–381.

    Article  CAS  PubMed  Google Scholar 

  • Golubnitschaja-Labudova O, Liu R, Decker C, Zhu P, Haefliger IO, et al. 2000. Altered gene expression in lymphocytes of patients with normal-tension glaucoma. Curr Eye Res 21: 867–876.

    Article  CAS  PubMed  Google Scholar 

  • Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML. 2000. The DNA sequence of human chromosome 21. Nature 405: 311–319.

    Article  CAS  PubMed  Google Scholar 

  • Hermon M, Cairns N, Egly JM, Fery A, Labudova O, et al. 1998. Expression of DNA excision-repair-cross-complementing proteins p80 and p89 in brain of patients with Down Syndrome and Alzheimer's disease. Neurosci Lett 251: 45–48.

    Article  CAS  PubMed  Google Scholar 

  • Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, et al. 1997. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc Natl Acad Sci USA 94: 3633–3638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, et al. 2000. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 67: 623–630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong CJ, Wang YC, Liu TY, Liu HC, Tsai SJ. 2001. A study of alpha-adrenoceptor gene polymorphisms and Alzheimer disease. J Neural Transm 108: 445–450.

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Rambaldi I, Daniels E, Featherstone M. 2003. Expression of the Wdr9 gene and protein products during mouse development. Dev Dyn 227: 608–614.

    Article  CAS  PubMed  Google Scholar 

  • James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, et al. 1999. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr 70: 495–501.

    Article  CAS  PubMed  Google Scholar 

  • Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, et al. 2004. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci USA 101: 343–347.

    Article  CAS  PubMed  Google Scholar 

  • Kamino K, Nagasaka K, Imagawa M, Yamamoto H, Yoneda H, et al. 2000. Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population. Biochem Biophys Res Commun 273: 192–196.

    Article  CAS  PubMed  Google Scholar 

  • Kim SH, Vlkolinsky R, Cairns N, Lubec G. 2000. Decreased levels of complex III core protein 1 and complex V beta chain in brains from patients with Alzheimer's disease and Down syndrome. Cell Mol Life Sci 57: 1810–1816.

    Article  CAS  PubMed  Google Scholar 

  • Labudova O, Krapfenbauer K, Moenkemann H, Rink H, Kitzmuller E, et al. 1998a. Decreased transcription factor junD in brains of patients with Down syndrome. Neurosci Lett 252: 159–162.

    Article  CAS  PubMed  Google Scholar 

  • Labudova O, Fang-Kircher S, Cairns N, Moenkemann H, Yeghiazaryan K, et al. 1998b. Brain vasopressin levels in Down syndrome and Alzheimer's disease. Brain Res 806: 55–59.

    Article  CAS  PubMed  Google Scholar 

  • Labudova O, Schuller E, Yeghiazarjan K, Kitzmueller E, Hoeger H, et al. 1999a. Genes involved in the pathophysiology of perinatal asphyxia. Life Sci 64: 1831–1838.

    Article  CAS  PubMed  Google Scholar 

  • Labudova O, Kitzmueller E, Rink H, Cairns N, Lubec G. 1999b. Gene expression in fetal Down syndrome brain as revealed by subtractive hybridization. J Neural Transm Suppl 57: 125–136.

    CAS  PubMed  Google Scholar 

  • Labudova O, Kitzmueller E, Rink H, Cairns N, Lubec G. 1999c. Increased phosphoglycerate kinase in the brains of patients with Down's syndrome but not with Alzheimer's disease. Clin Sci (Lond) 96: 279–285.

    Article  CAS  Google Scholar 

  • Labudova O, Cairns N, Kitzmuller E, Lubec G. 1999d. Impaired brain glucose metabolism in patients with Down syndrome. J Neural Transm Suppl 57: 247–256.

    CAS  PubMed  Google Scholar 

  • Labudova O, Cairns N, Koeck T, Kitzmueller E, Rink H, et al. 1999e. Thyroid stimulating hormone-receptor overexpression in brain of patients with Down syndrome and Alzheimer's disease. Life Sci 64: 1037–1044.

    Article  CAS  PubMed  Google Scholar 

  • Lubec G, Labudova O, Cairns N, Fountoulakis M. 1999a. Increased glyceraldehyde 3-phosphate dehydrogenase levels in the brain of patients with Down's syndrome. Neurosci Lett 260: 141–145.

    Article  CAS  PubMed  Google Scholar 

  • Lubec G, Labudova O, Cairns N, Berndt P, Langen H, et al. 1999b. Reduced aldehyde dehydrogenase levels in the brain of patients with Down syndrome. J Neural Transm Suppl57: 21–40.

    Google Scholar 

  • Ma Z, Morris SW, Valentine V, Li M, Herbrick JA, et al. 2001. Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28: 220–221.

    Article  CAS  PubMed  Google Scholar 

  • Murphy TC, Amarnath V, Gibson KM, Picklo MJ Sr. 2003. Oxidation of 4-hydroxy-2-nonenal by succinic semialdehyde dehydrogenase (ALDH5A). J Neurochem 86: 298–305.

    Article  CAS  PubMed  Google Scholar 

  • Nagele RG, D'Andrea MR, Anderson WJ, Wang HY. 2002. Intracellular accumulation of beta-amyloid(1–42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer's disease. Neuroscience 110: 199–211.

    Article  CAS  PubMed  Google Scholar 

  • Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K. 1991. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res 541: 163–166.

    Article  CAS  PubMed  Google Scholar 

  • Panoutsopoulos GI, Kouretas D, Beedham C. 2004. Contribution of aldehyde oxidase, xanthine oxidase, and aldehyde dehydrogenase on the oxidation of aromatic aldehydes. Chem Res Toxicol 17: 1368–1376.

    Article  CAS  PubMed  Google Scholar 

  • Paoloni-Giacobino A, Chen H, Antonarakis SE. 1997. Cloning of a novel human neural cell adhesion molecule gene (NCAM2) that maps to chromosome region 21q21 and is potentially involved in Down syndrome. Genomics 43: 43–51.

    Article  CAS  PubMed  Google Scholar 

  • Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, et al. 2001. Homocysteine metabolism in children with Down  syndrome: In vitro modulation. Am J Hum Genet 69: 88–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reinikainen KJ, Pitkanen A, Riekkinen PJ. 1989. 2′,3′-cyclic nucleotide-3′-phosphodiesterase activity as an index of myelin in the post-mortem brains of patients with Alzheimer's disease. Neurosci Lett 106: 229–232.

    Article  CAS  PubMed  Google Scholar 

  • Ristow M. 2004. Neurodegenerative disorders associated with diabetes mellitus. J Mol Med 82: 510–529.

    Article  PubMed  Google Scholar 

  • Schapiro MB, Haxby JV, Grady CL. 1992. Nature of mental retardation and dementia in Down syndrome: Study with PET, CT, and neuropsychology. Neurobiol Aging 13: 723–734.

    Article  CAS  PubMed  Google Scholar 

  • Seidl R, Labudova O, Krapfenbauer K, Henriksson EW, Craft J, et al. 2001. Deficient brain snRNP70K in patients with Down syndrome. Electrophoresis 22: 43–48.

    Article  CAS  PubMed  Google Scholar 

  • Sive HL, St John T. 1988. A simple subtractive hybridization technique employing photoactivatable biotin and phenol extraction. Nucleic Acids Res 16: 10937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slominski A, Pisarchik A, Semak I, Sweatman T, Wortsman J. 2003. Characterization of the serotoninergic system in the C57BL/6 mouse skin. Eur J Biochem 270: 3335–3344.

    Article  CAS  PubMed  Google Scholar 

  • Snow AD, Wight TN. 1989. Proteoglycans in the pathogenesis of Alzheimer's disease and other amyloidoses. Neurobiol Aging 10: 481–497.

    Article  CAS  PubMed  Google Scholar 

  • Sodhi MS, Sanders-Bush E. 2004. Serotonin and brain development. Int Rev Neurobiol 59: 111–174.

    Article  CAS  PubMed  Google Scholar 

  • Stocchi V, Magnani M, Cucchiarini L, Novelli G, Dallapiccola B. 1985. Red blood cell adenine nucleotides abnormalities in Down syndrome. Am J Med Genet 20: 131–135.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi S, Makita Y, Okamoto N, Miyamoto A, Oki J. 1997. L1CAM mutation in a Japanese family with X-linked hydrocephalus: A study for genetic counseling. Brain Dev 19: 559–562.

    Article  CAS  PubMed  Google Scholar 

  • Vlkolinsky R, Cairns N, Fountoulakis M, Lubec G. 2001. Decreased brain levels of 2′,3′-cyclic nucleotide-3′-phosphodiesterase in Down syndrome and Alzheimer's disease. Neurobiol Aging 22: 547–553.

    Article  CAS  PubMed  Google Scholar 

  • Willemsen MA, Ijlst L, Steijlen PM, Rotteveel JJ, de Jong JG, et al. 2001. Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjogren-Larsson syndrome. Brain 124: 1426–1437.

    Article  CAS  PubMed  Google Scholar 

  • Yeghiazaryan K, Turhani‐Schatzmann D, Labudova O, Schuller E, Olson EN, Cairns N, Lubec G. 1999. Downregulation of the transcription factor scleraxis in brain of patients with Down syndrome. J Neural Transm Suppl 57: 305–314.

    CAS  PubMed  Google Scholar 

  • Zipursky A, Poon A, Doyle J. 1992. Leukemia in Down syndrome: A review. Pediatr Hematol Oncol 9: 139–149.

    Article  CAS  PubMed  Google Scholar 

Download references

Authors
  1. O. Golubnitschaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Fountoulakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, New York, 10962, Orangeburg, USA

    Abel Lajtha (Director) (Director)

  2. Technion‐Rappaport Family Faculty of Medicine, Efron St., POBox 9697, 31096, Haifa, Israel

    Moussa B. H. Youdim (Professor of Pharmacology Professor of Life Sciences Director of Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Research) (Professor of Pharmacology Professor of Life Sciences Director of Eve Topf and NPF Centers of Excellence for Neurodegenerative Diseases Research)

  3. Clinic and Policlinic of Psychiatry and Psychotherapy Dept. Clinical Neurochemistry, University of Würzburg, Füchsleinstr. 15, 97080, Würzburg, Germany

    Peter Riederer

  4. Eve Topf Center for Neurodegenerative Diseases Research and Dept. of Pharmacology, Faculty of Medicine Technion, Efron St., P.O.B. 9697, 31096, Haifa, Israel

    Sylvia A. Mandel

  5. Department of Neurosciences, University of Padova Medical School, Via Giustiniani 5, 35128, Padova, Italy

    Leontino Battistin

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer Science+Business Media, LLC

About this entry

Cite this entry

Golubnitschaja, O., Fountoulakis, M. (2007). Gene Hunting by Substractive Hybridization in Down Syndrome Correlation with Proteomics Analysis. In: Lajtha, A., Youdim, M.B.H., Riederer, P., Mandel, S.A., Battistin, L. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, New York, NY. https://doi.org/10.1007/978-0-387-30377-2_16

Download citation

Publish with us

Policies and ethics

Search

Navigation