Aberrant protein expression of transcription factors BACH1 and ERG, both encoded on chromosome 21, in brains of patients with Down syndrome and Alzheimer’s disease

  • K. S. Shim
  • R. Ferrando-Miguel
  • G. Lubec
Part of the Journal of Neural Transmission Supplement 67 book series (NEURAL SUPPL, volume 67)


Down syndrome (DS; trisomy 21) is a genetic disorder associated with early mental retardation and patients inevitably develop Alzheimer’s disease (AD)-like neuropathological changes. The molecular defects underlying the DS — phenotype may be due to overexpression of genes encoded on chromosome 21. This so-called gene dosage hypothesis is still controversial and demands systematic work on protein expression. A series of transcription factors (TF) are encoded on chromosome 21 and are considered to play a pathogenetic role in DS. We therefore decided to study brain expression of TF encoded on chromosome 21 in patients with DS and AD compared to controls: Frontal cortex of 6 male DS patients, 6 male patients with AD and 6 male controls were used for the experiments. Immunoblotting was used to determine protein levels of TF BACH1, ERG, SIM2 and RUNX1. SIM2 and RUNX1 were comparable between groups, while BACH1 was significantly reduced in DS, and ERG was increased in DS and AD as compared to controls. These findings may indicate that DS pathogenesis cannot be simply explained by the gene dosage effect hypothesis and that results of ERG expression in DS were paralleling those in AD probably reflecting a common pathogenetic mechanism possibly explaining why all DS patients develop AD like neuropathology from the fourth decade. We conclude that TF derangement is not only due to the process of neurodegeneration and propose that TFs BACH1 and ERG play a role for the development of AD — like neuropathology in DS and pathogenesis of AD per se and the manifold increase of ERG in both disorders may form a pivotal pathogenetic link.


Down Syndrome Down Syndrome Patient Common Pathogenetic Mechanism Fetal Down Syndrome Fetal Liver Hematopoiesis 
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  1. Asou N (2003) The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications. Crit Rev Oncol Hematol 45: 129–150PubMedCrossRefGoogle Scholar
  2. Aziz-Aloya RB, Levanon D, Kam H, Kidron D, Goldenberg D, Lotem J, Polak-Chaklon S, Groner Y (1998) Expression of AML1-d, a short human AML1 isoform, in embryonic stem cells suppresses in vivo tumor growth and differentiation. Cell Death Differ 5: 765–773PubMedCrossRefGoogle Scholar
  3. Basuyaux JP, Ferreira E, Stehelin D, Buttice G (1997) The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner J Biol Chem 272: 26188–26195Google Scholar
  4. Bernardin F, Friedman AD (2002) AML1 stimulates G1 to S progression via its transactivation domain. Oncogene 21: 3247–3252PubMedCrossRefGoogle Scholar
  5. Blom N, Gammeltoft S, Brunak S (1999) Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol 294: 1351–1362PubMedCrossRefGoogle Scholar
  6. Cairns NJ (1999) Neuropathology. J Neural Transm [Suppl] 57: 61–74Google Scholar
  7. Cheon MS, Bajo M, Kim SH, Claudio JO, Stewart AK, Patterson D, Kruger WD, Kondoh H, Lubec G (2003) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: challenging the gene dosage effect hypothesis, part II Amino Acids 24: 119–125Google Scholar
  8. Cheon MS, Kim SH, Ovod V, Kopitar Jerala N, Morgan JI, Hatefi Y, Ijuin T, Takenawa T, Lubec G (2003) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: challenging the gene dosage effect hypothesis, part III Amino Acids 24: 127–134Google Scholar
  9. Cheon MS, Kim SH, YaspoML, Blasi F, Aoki Y, Melen K, Lubec G (2003) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: challenging the gene dosage effect hypothesis, part I. Amino Acids 24: 111–117PubMedGoogle Scholar
  10. Cheon MS, Shim KS, Kim SH, Hara A, Lubec G (2003) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: challenging the gene dosage effect hypothesis, part IV. Amino Acids 25: 41–47PubMedGoogle Scholar
  11. Chrast R, Scott HS, Madani R, Huber L, Wolfer DP, Prinz M, Aguzzi A, Lipp HP, Antonarakis SE (2000) Mice trisomic for a bacterial artificial chromosome with the single-minded 2 gene (Sim2) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome. Hum Mol Genet 9: 1853–1864PubMedCrossRefGoogle Scholar
  12. Erna M, Ikegami S, Hosoya T, Mimura J, Ohtani H, Nakao K, Inokuchi K, Katsuki M, Fujii-Kuriyama Y (1999) Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down’s syndrome. Hum Mol Genet 8: 1409–1415CrossRefGoogle Scholar
  13. Engidawork E, Lubec G (2003) Molecular changes in fetal Down syndrome brain. J Neurochem 84: 895–904PubMedCrossRefGoogle Scholar
  14. Engidawork E, Balic N, Fountoulakis M, Dierssen M, Greber-Platzer S, Lubec G (2001) Beta-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 [Suppl] 61: 335–346Google Scholar
  15. 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 749–794Google Scholar
  16. Fan CM, Kuwana E, Bulfone A, Fletcher CF, Copeland NG, Jenkins NA, Crews S, Martinez S, Puelles L, Rubenstein LR, Tessier-Lavigne M (1996) Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome. Mol Cell Neurosci 7: 1–16PubMedCrossRefGoogle Scholar
  17. Fang-Kircher SG, Labudova O, Kitzmueller E, Rink H, Cairns N, Lubec G (1999) Increased steady state mRNA levels of DNA-repair genes XRCC1, ERCC2 and ERCC3 in brain of patients with Down syndrome. Life Sci 64: 1689–1699PubMedCrossRefGoogle Scholar
  18. Ferrando-Miguel R, Lubec G (2003) Overexpression of transciption factor BACH1 in fetal Down syndrome brain. J Neural Transm [Suppl] 67 (this volume)Google Scholar
  19. Freidl M, Gulesserian T, Lubec G, Fountoulakis M, Lubec B (2001) Deterioration of the transcriptional, splicing and elongation machinery in brain of fetal Down syndrome. J Neural Transm [Suppl] 61: 47–57Google Scholar
  20. Greber-Platzer S, Balcz B, Cairns N, Lubec G (1999) c-fos expression in brains of patients with Down syndrome. J Neural Transm [Suppl] 57: 75–85Google Scholar
  21. Guenal I, Risler Y, Mignotte B (1997) Down-regulation of actin genes precedes microfilament network disruption and actin cleavage during p53-mediated apoptosis. J Cell Sci 110: 489–495PubMedGoogle Scholar
  22. Gulesserian T, Engidawork E, Fountoulakis M, Lubec G (2001) Antioxidant proteins in fetal brain: superoxide dismutase-1 (SOD-1) protein is not overexpressed in fetal Down syndrome. J Neural Transm [Suppl] 61: 71–84Google Scholar
  23. He X, Rosenfeld MG (1991) Mechanisms of complex transcriptional regulation: implications for brain development. Neuron 7: 183–196PubMedCrossRefGoogle Scholar
  24. Hewett PW, Nishi K, Daft EL, Clifford Murray J (2001) Selective expression of erg isoforms in human endothelial cells. Int J Biochem Cell Biol 33: 347–355PubMedCrossRefGoogle Scholar
  25. Katsuoka F, Motohashi H, Tamagawa Y, Kure S, Igarashi K, Engel JD, Yamamoto M (2003) Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response. Mol Cell Biol 23: 1163–1174PubMedCrossRefGoogle Scholar
  26. Kitamuro T, Takahashi K, Ogawa K, Udono-Fujimori R, Takeda K, Furuyama K, Nakayama M, Sun J, Fujita H, Hida W, Hattori T, Shirato K, Igarashi K, Shibahara S (2003) Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells. J Biol Chem 278: 9125–9133PubMedCrossRefGoogle Scholar
  27. Labudova O, Krapfenbauer K, Moenkemann H, Rink H, Kitzmuller E, Cairns N, Lubec G (1998) Decreased transcription factor junD in brains of patients with Down syndrome. Neurosci Lett 252: 159–162PubMedCrossRefGoogle Scholar
  28. Labudova O, Kitzmueller E, Rink H, Cairns N, Lubec G (1999) Gene expression in fetal Down syndrome brain as revealed by subtractive hybridization. J Neural Transm [Suppl] 57: 125–136Google Scholar
  29. LeBlanc A (1998) Detection of actin cleavage in Alzheimer’s disease. Am J Pathol 152: 329–332Google Scholar
  30. Levanon D, Brenner O, Negreanu V, Bettoun D, Woolf E, Eilam R, Lotem J, Gat U, Otto F, Speck N, Groner Y (2001) Spatial and temporal expression pattern of Runx3 (Am12) and Runxl (Am11) indicates non-redundant functions during mouse embryo-genesis. Mech Dev 109: 413–417PubMedCrossRefGoogle Scholar
  31. Lubec G, Engidawork E (2002) The brain in Down syndrome (TRISOMY 21). J Neurol 249: 1347–1356PubMedCrossRefGoogle Scholar
  32. Maroulakou IG, Bowe DB (2000) Expression and function of Ets transcription factors in mammalian development: a regulatory network. Oncogene 19: 6432–6442PubMedCrossRefGoogle Scholar
  33. Mazzola JL, Sirover MA (2002) Alteration of intracellular structure and function of glyceraldehyde-3-phosphate dehydrogenase: a common phenotype of neurodegenerative disorders. Neurotoxicology 23: 603–609PubMedCrossRefGoogle Scholar
  34. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Part 2 Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41: 479–486PubMedCrossRefGoogle Scholar
  35. Moffett P, Dayo M, Reece M, McCormick MK, Pelletier J (1996) Characterization of msim, a murine homologue of the Drosophila sim transcription factor. Genomics 35: 144–155PubMedCrossRefGoogle Scholar
  36. Muenke M, Bone LJ, Mitchell HF, Hart I, Walton K, Hall-Johnson K, Ippel EF, Dietz-Band J, Kvaloy K, Fan CM (1995) Physical mapping of the holoprosencephaly critical region in 21q22.3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping of SIM2 to a region of chromosome 21 important for Down syndrome. Am J Hum Genet 57: 1074–1079PubMedGoogle Scholar
  37. Nicham R, Weitzdörfer R, Hauser E, Freidl M, Schubert M, Wurst E, Lubec G, Seidl R (2003) Spectrum of cognitive, behavioural and emotional problems in children and young adults with Down syndrome. J Neural Transm [Suppl 67] (this volume)Google Scholar
  38. Ogawa K, Sun J, Taketani S, Nakajima O, Nishitani C, Sassa S, Hayashi N, Yamamoto M, Shibahara S, Fujita H, Igarashi K (2001) Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bachl. EMBO J 20: 2835–2843PubMedCrossRefGoogle Scholar
  39. Okuda T, van Deursen J, Hiebert JW, Grosveld G, Downing JR (1996) AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84: 321–330PubMedCrossRefGoogle Scholar
  40. Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M, Yamamoto M, Igarashi K (1996) Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol Cell Biol 16: 6083–6095PubMedGoogle Scholar
  41. Perry C, Eldor A, Soreq H (2002) Runxl/AML1 in leukemia: disrupted association with diverse protein partners. Leuk Res 26: 221–228PubMedCrossRefGoogle Scholar
  42. Perry C, Sklan EH, Birikh K, Shapira M, Trejo L, Eldor A, Soreq H (2002) Complex regulation of acetylcholinesterase gene expression in human brain tumors. Oncogene 21: 8428–8441PubMedCrossRefGoogle Scholar
  43. Sawa A (1999) Neuronal cell death in Down’s syndrome. J Neural Transm [Suppl] 57: 87–97Google Scholar
  44. Schipper HM (2000) Heme oxygenase-1: role in brain aging and neurodegeneration. Exp Gerontol 35: 821–830PubMedCrossRefGoogle Scholar
  45. Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, Tashiro S, Takahashi S, Shibahara S, Alam J, Taketo MM, Yamamoto M, Igarashi K (2002) Hemoprotein Bachl regulates enhancer availability of heme oxygenase-1 gene. EMBO J 21: 5216–5224PubMedCrossRefGoogle Scholar
  46. Tierney MC, Fisher RH, Lewis AJ, Zorzitto ML, Snow WG, Reid DW, Nieuwstraten P (1998) The NINCDS-ADRDA Work Group criteria for the clinical diagnosis of probable Alzheimer’s disease: a clinicopathologic study of 57 cases. Neurology 38: 359–364CrossRefGoogle Scholar
  47. Trojanowska M (2000) Ets factors and regulation of the extracellular matrix. Oncogene 19: 6464–6471PubMedCrossRefGoogle Scholar
  48. Tsuji K, Noda M (2000) Identification and expression of a novel 3’-exon of mouse Runxl/ Pebp2 alphaB/Cbfa2/AML1 gene. Biochem Biophys Res Commun 274: 171–176PubMedCrossRefGoogle Scholar
  49. Verger A, Buisine E, Carrere S, Wintjens R, Flourens A, Coll J, Stehelin D, DuterqueCoquillaud M (2000) Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation. J Biol Chem 276: 17181–17189CrossRefGoogle Scholar
  50. Vialard F, Toyama K, Vernoux S, Carlson EJ, Epstein CJ, Sinet PM, Rahmani Z (2000) Overexpression of mSim2 gene in the zona limitans of the diencephalon of segmental trisomy 16 Ts1Cje fetuses, a mouse model for trisomy 21: a novel whole-mount based RNA hybridization study. Brain Res Dev Brain Res 121: 73–78PubMedCrossRefGoogle Scholar
  51. Westendorf JJ, Hiebert SW (1999) Mammalian runt-domain proteins and their roles in hematopoiesis, osteogenesis, and leukaemia. J Cell Biochem [Suppl] 32: 51–58CrossRefGoogle Scholar
  52. Yang L, Xia L, Wu DY, Wang H, Chansky HA, Schubach WH, Hickstein DD, Zhang Y (2002) Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. Oncogene 21: 148–152PubMedCrossRefGoogle Scholar
  53. 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: 305–314Google Scholar
  54. Yi H, Fujimura Y, Ouchida M, Prasad DD, Rao VN, Reddy ES (1997) Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias. Oncogene 14: 1259–1268PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • K. S. Shim
    • 1
  • R. Ferrando-Miguel
    • 2
  • G. Lubec
    • 1
    • 3
  1. 1.Department of PediatricsUniversity of ViennaViennaAustria
  2. 2.Department of NeonatologyUniversity of ViennaViennaAustria
  3. 3.CChem, FRSC (UK), Department of PediatricsUniversity of ViennaViennaAustria

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