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β-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

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Summary

Down syndrome (DS) is the most common human chromosomal abnormality caused by an extra copy of chromosome 21 and characterized clinically by somatic anomalies, mental retardation and precocious dementia. The phenotype of DS is thought to result from overexpression of a gene or genes located on the triplicated chromosome or chromosome region. Reports that challenge this notion, however, have been published. To add to this body of evidence, the expression of β-amyloid precursor protein (APP), ETS-2 and collagen α1 (VI) chain precursor, encoded on chromosome 21, was investigated in fetal brain by western blot and two-dimensional electrophoresis (2-DE). Western blot detected APP and ETS-2 that migrated at -75 and 50kDa, respectively. Subsequent densitometric analysis of APP and ETS-2 immuno-reactivity did not produce any significant change between controls and DS. Since the metabolic fate of APP determines the propensity of amyloid β production, the expression of the secreted forms of APP (sAPP) had been examined. Neither the expression of sAPPaα nor sAPPß showed any detectable changes among the two groups. Collagen α1(VI) chain precursor, a protein resolved as a single spot on 2D gel was identified by matrix associated laser desorption ionization mass spectroscopy. Quantitative analysis of this spot using the 2D Image Master software revealed a significant decrease in fetal DS (P < 0.01) compared to controls. Linear regression analysis did not show any correlation between protein levels and age. The current data suggest that overexpression per se can not fully explain the DS phenotype.

Keywords

  • Down Syndrome
  • Amyloid Precursor Protein
  • Gene Dosage Effect
  • Down Syndrome Patient
  • Amyloid Precursor Protein Gene

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  • Antonarakis SE (1998) 10 years of genomics, chromosome 21, and Down syndrome. Genomics 51: 1–16

    PubMed  CrossRef  CAS  Google Scholar 

  • Arai Y, Suzuki A, Mizuguchi M, Takashima S (1997) Developmental and aging changes in the expression of amyloid precursor protein in Down syndrome brains. Brain Dev 19: 290–294

    PubMed  CrossRef  CAS  Google Scholar 

  • Baffico M, Perroni L, Rasore-Quartino A, Scartezzini P (1989) Expression of the human ETS-2 oncogene in normal fetal tissues and in the brain of a fetus with trisomy 21. Hum Genet 83: 295–296

    PubMed  CrossRef  CAS  Google Scholar 

  • Berndt P, Hobohm U, Langen H (1999) Reliable automatic protein identification from matrix-assisted laser desorption/ionization mass spectrometric peptide fingerprints. Electrophoresis 20: 3521–3526

    PubMed  CrossRef  CAS  Google Scholar 

  • Bhat NK, Fisher RJ, Fujiwara S, Ascione R, Papas TS (1987) Temporal and tissue specific expression of mouse ETS genes. Proc Natl Acad Sci USA 84: 3161–3165

    PubMed  CrossRef  CAS  Google Scholar 

  • 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: 248–254

    PubMed  CrossRef  CAS  Google Scholar 

  • Brown JC, Timpl R (1995) The collagen superfamily. Int Arch Allerg Appl Immunol 107: 484–490

    CrossRef  CAS  Google Scholar 

  • Chu M-L, Conway D, Pan T-C, Baldwin C, Mann K, Deutzmann R, Timpl R (1988) Amino acid sequence of the triple helical domain of the human collagen type VI. J Biol Chem 263: 18601–18606

    PubMed  CAS  Google Scholar 

  • 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: 379–402

    PubMed  CrossRef  Google Scholar 

  • Epstein CJ (1995) Down Syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 7th edn, vol. I. McGraw Hill,New York, pp 749–794

    Google Scholar 

  • Fountoulakis M, Langen H (1997) Identification of proteins by matrix assisted laser desorption ionization mass spectrometry following in-gel digestion in low salt, nonvolatile buffer and simplified peptide recovery. Anal Biochem 250: 153–156

    PubMed  CrossRef  CAS  Google Scholar 

  • Furthmayr H, Wiedemann H, Timpl R, Odermatt E, Engel J (1983) Electron microscopical approach to a structural model of intima collagen. Biochem J 211: 303–311

    PubMed  CAS  Google Scholar 

  • Golaz J, Charnay Y, Vallet P, Bouras C (1991) Alzheimer’s disease and Down syndrome.Some recent etiopathogenic data. Encephale 17: 29–31

    PubMed  CAS  Google Scholar 

  • Greber-Platzer S, Schatzmann-Turhani D, Wollenek G, Lubec G (1998) Evidence against the current hypothesis of “gene dosage effects” of trisomy 21: ETS-2, encoded on chromosome 21 is not overexpressed in hearts of patients with Down syndrome.Biochem Biophys Res Commun 254: 395–399

    CrossRef  Google Scholar 

  • Greber-Platzer S, Schatzmann-Turhani D, Cairns D, Balcz B, Lubec G (1999) Expression of the transcription factor ETS-2 in brain of patients with Down syndrome-evidence against the overexpression gene hypothesis. J Neural Transm [Suppl] 57: 269–281

    CAS  Google Scholar 

  • Griffin WST, Sheng JG, McKenzie LE, Royston MC, Gentleman SM, Brumback RA,Cork LC, Del Bigio MR, Roberts GW, Mrak RE (1998) Life-long expression of S-100ß in Down’s syndrome: implication for Alzheimer pathogenesis. Neurobiol Aging 19: 401–405

    PubMed  CrossRef  CAS  Google Scholar 

  • Hatori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park H-S et al (2000) The DNA sequence of human chromosome 21. Nature 405: 311–319

    CrossRef  Google Scholar 

  • Howlett DR, James S, Allsop D, Roberts GW (1995) The biology and molecular pathology of β.amyloid protein. In: Dawbarn D, Allen SJ (eds) Neurobiology of Alzheimer’s disease. BIOS Scientific Publishers, Oxford, pp 9–49

    Google Scholar 

  • Jander R, Raterberg J, Glanville RW (1983) Further characterization of the three polypeptide chains of bovine and human short-chain collagen (intima collagen). Eur J Biochem 133: 39–46

    PubMed  CrossRef  CAS  Google Scholar 

  • Kang J, Lemaire H-G, Unterbeck A, Salbaum JM, Masters CL, Grezeschik K-H,Multhaup G, Beyreuther K, Müller-Hill B (1987) The precursor of Alzheimer’s amyloid A4 protein resembles a cell surface receptor. Nature 325: 733–736

    PubMed  CrossRef  CAS  Google Scholar 

  • Klewer SE, Krob SL, Kolker SJ, Kitten GT (1998) Expression of type VI collagen in the developing mouse heart. Dev Dyn 211: 248–255

    PubMed  CrossRef  CAS  Google Scholar 

  • Knupp C, Squire JM (2001) A new twist in the collagen story - the type VI segmented supercoil. EMBO J 20: 372–376

    PubMed  CrossRef  CAS  Google Scholar 

  • Lamande SR, Shields KA, Kornberg AJ, Shield LK, Bateman JF (1999) Bethlem myopathy and engineered collagen VI triple helical deletion prevent intracellular multimer assembly and protein secretion. J Biol Chem 274: 21817–21822

    PubMed  CrossRef  CAS  Google Scholar 

  • 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: 2085–2090

    PubMed  CrossRef  CAS  Google Scholar 

  • Levine JM, Nishiyama A (1996) The NG-2 chondrotin sulfate proteoglycan: a multi functional proteoglycan associated with immature cells. Perspect Dev Biol 3: 545–559

    CAS  Google Scholar 

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

    PubMed  CrossRef  CAS  Google Scholar 

  • Maraoulakou IG, Papas TS, Green JE (1994) Differential expression of ETS-1 and ETS-2 genes during murine embriogenesis. Oncogene 9: 1551–1565

    Google Scholar 

  • Mills J, Reiner PB (1999) Regulation of amyloid precursor protein cleavage. J Neurochem 72: 443–460

    PubMed  CrossRef  CAS  Google Scholar 

  • Neve RL, Finch EA, Dawes LR (1988) Expression of the Alzheimer’s amyloid precursor gene transcript in the human brain. Neuron 1: 669–677

    PubMed  CrossRef  CAS  Google Scholar 

  • Neve RL, McPhie DL, Chen Y (2000) Alzheimer’s disease: a dysfunction of the amyloid precursor protein. Brain Res 886: 54–66

    PubMed  CrossRef  CAS  Google Scholar 

  • Oyama F, Cairns NJ, Shaimada H, Oyama R, Titani K, Inara Y (1994) Down’s syndrome: upregulation of β-amyloid protein precursor and tau mRNAs and their defective coordination. J Neurochem 62: 1062–1066

    PubMed  CrossRef  CAS  Google Scholar 

  • Pellegrini L, Passer BJ, Tabaton M, Ganjei JK, D’Adamio L (1999) Alternative non-secretase processing of Alzheimer’s β-amyloid precursor protein during apoptosis by caspase-6 and -8. J Biol Chem 274: 21011–21016

    PubMed  CrossRef  CAS  Google Scholar 

  • Pritchard MA, Kola I (1999) The “gene dosage effect” versus the “amplified developmental instability” hypothesis in Down syndrome. J Neural Transm [Suppl] 57: 293–303

    CAS  Google Scholar 

  • Shapiro BL (1983) Down syndrome - a disruption of homeostasis. Am J Med Genet 14: 241–269

    PubMed  CrossRef  CAS  Google Scholar 

  • Shapiro BL (1999) The Down syndrome critical region. J Neural Transm [Suppl] 57: 41–60

    CAS  Google Scholar 

  • Sumarsono SH, Wilson TJ, Tymms MJ, Venter D, Corrick CM, Kola R, Lahoud M, Papas TS, Seth A, Kola I (1996) Ets transgenic mice develop skeletal abnormalities analogous to those found in Down syndrome. Nature 379: 534–537

    PubMed  CrossRef  CAS  Google Scholar 

  • Teller JK, Russo C, DeBusk LM, Angelini G, Zaccheo D, Dagna-Bricarelli F, Scartezzini P, Bertolini S, Mann DMA, Tabaton M, Gambetti P (1996) Presence of soluble amyloid β-peptide precedes amyloid plaque formation in Down’s syndrome. Nature Med 2: 93–95

    PubMed  CrossRef  CAS  Google Scholar 

  • Trüeb B, Bornstein P (1984) Characterization of the precursor form of type VI collagen. J Biol Chem 259: 8597–8604

    PubMed  Google Scholar 

  • von Kaisenberg CS, Brand-Saberi B, Christ B, Vallian S, Farzaneh F, Nicolaides KH (1998) Collagen type VI expression in the skin of trisomy 21 fetuses. Obstet Gynecol 91: 319–323

    CrossRef  Google Scholar 

  • Wasco W, Tanzi RE (1995) Molecular genetics of amyloid and apolipoprotein E in Alzheimer’s disease. In: Dawbarn D, Allen SJ (eds) Neurobiology of Alzheimer’s disease. BIOS Scientific Publishers, Oxford, pp 51–76

    Google Scholar 

  • Wasylyk B, Hahn SL, Giovane A (1993) The ETS family transcription factors. Eur J Biochem 211: 7–18

    PubMed  CrossRef  CAS  Google Scholar 

  • Weil D, Mattei MG, Passage E, N’Guyen VC, Pribula-Conway D, Mann K, Deutzmann R, Timpl R, Chu ML (1988) Cloning and chromosomal localization of human genes encoding the three chains of type VI collagen. Am J Hum Genet 42: 435–445

    PubMed  CAS  Google Scholar 

  • Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down syndrome. Ann Neurol 17: 278–282

    PubMed  CrossRef  CAS  Google Scholar 

  • Yoshikai S-I, Sasaki H, Doh-ura K, Furuya H, Sakaki Y (1990) Genomic organization of the human amyloid beta protein precursor gene. Gene 87: 257–263

    PubMed  CrossRef  CAS  Google Scholar 

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Engidawork, E., Balic, N., Fountoulakis, M., Dierssen, M., Greber-Platzer, S., Lubec, G. (2001). β-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. In: Lubec, G. (eds) Protein Expression in Down Syndrome Brain. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6262-0_28

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  • DOI: https://doi.org/10.1007/978-3-7091-6262-0_28

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-211-83704-7

  • Online ISBN: 978-3-7091-6262-0

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