Molecular misreading of genes in Down syndrome as a model for the Alzheimer type of neurodegeneration

  • F. W. van Leeuwen
  • E. M. Hol
Conference paper


The occurrence of +1 frameshifted proteins, such as amyloid precursor protein (APP+1) and ubiquitin-B (UBB+1) in Down syndrome (DS) has been linked to the onset of Alzheimer’s disease (AD). In DS and AD patients, but also in elderly non-demented persons, these co-called +1 proteins accumulate in the neuropathological hallmarks (neurofibrillary tangles, dystrophic neuntes of the neuritic plaques and neuropil threads) and may have deleterious effects on neuronal function. Frameshifts are caused by dinucleotide deletions in GAGAG motifs in messenger RNA and are now thought to be the result of unfaithful transcription of normal DNA by a novel process termed “molecular misreading”. In the present review some of the critical events in molecular misreading are discussed, the emphasis being on DS.


Down Syndrome Paired Helical Filament Down Syndrome Patient Neuropil Thread mRNA Surveillance 
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  1. Adams MD, Dubnick M, Kerlavage AR, Moreno R, Kelley JM, Utterback TR, Nagle JW, Fields C, Venter JC (1992) Sequence identification of 2,375 human brain genes. Nature 355: 632–634PubMedCrossRefGoogle Scholar
  2. Antonarakis SE (1998) 10 Years of genomics, chromosome 21, and Down syndrome. Genomics 51: 1–16PubMedCrossRefGoogle Scholar
  3. Applequist SE, Selg M, Raman C, Jäck H-M (1997) Cloning and characterization of HUPF1, a human homolog of the Saccharomyces cerevisiae nonsense mRNA-reducing UPF1 protein. Nucl Acids Res 25: 814–821PubMedCrossRefGoogle Scholar
  4. Baker RT, Board PG (1987) The human ubiquitin gene family: structure of a gene and pseudogenes from the Ub B subfamily. Nucl Acids Res 15: 443–463PubMedCrossRefGoogle Scholar
  5. Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RCP, Perry R, Watson Jr B, Bassett SS, McInnis MG, Albert MS, Hyman BT, Tanzi RE (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nature Genet 19: 357–360PubMedCrossRefGoogle Scholar
  6. Braak H, Braak E, Yilmazer D, de Vos RAI, Jansen EHN, Bohl J (1996) Pattern of brain destruction in Parkinson’s disease and Alzheimer’s disease. J Neural Transm 103: 455–490PubMedCrossRefGoogle Scholar
  7. Ciechanover A (1998) The ubiquitin-proteasome pathway: on protein death and cell life. EMBO J 17: 7151–7160PubMedCrossRefGoogle Scholar
  8. Citron M, Haass C, Selkoe DJ (1993) Production of amyloid-β-peptide by cultured cells: no evidence for internal initiation of translation at Met596. Neurobiol Aging 14: 571–573PubMedCrossRefGoogle Scholar
  9. Cole GM, Masliah EM, Huyn TV, DeTeresa R, Terry RD, Okuda C, Saitoh T (1989) An antiserum against amyloid β-protein precursor detects a unique peptide in Alzheimer brain. Neurosci Lett 100: 340–346PubMedCrossRefGoogle Scholar
  10. Cole GM, Masliah E, Shelton ER, Chan HW, Terry RD, Saitoh T (1991) Accumulation of amyloid precursor fragment in Alzheimer plaques. Neurobiol Aging 12: 85–91PubMedCrossRefGoogle Scholar
  11. Cruts M, Van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C (1998) Estimation of the genetic contribution of presenilin-1 and-2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet 7: 43–51PubMedCrossRefGoogle Scholar
  12. Culbertson, MR (1999) RNA surveillance, unforseen consequences for gene expression, inherited genetic disorders and cancer. TIG 15: 74–79PubMedCrossRefGoogle Scholar
  13. Evans DAP, Van der Kleij AAM, Sonnemans MAF, Burbach JPH, Van Leeuwen FW (1994) Frameshift mutations at two hotspots in vasopressin transcripts in post-mitotic neurons. Proc Natl Acad Sci USA 91: 6059–6063PubMedCrossRefGoogle Scholar
  14. Evans DAP, Burbach JPH, Van Leeuwen FW (1995) Somatic mutations in the brain: relationship to aging? Mutat Res 338: 173–182PubMedCrossRefGoogle Scholar
  15. Evans DAP, Burbach JPH, Swaab DF, Van Leeuwen FW (1996) Mutant vassopressin precursors in the human hypothalamus: evidence for neuronal somatic mutations in man. Neuroscience 71: 1025–1030PubMedCrossRefGoogle Scholar
  16. Finch CE (1990) Longevity, senescence and the genome. University of Chicago Press, ChicagoGoogle Scholar
  17. Finch CE, Goodman MF (1997) Relevance of ‘adapative’ mutations arising in non-dividing cells of microorganisms to age-related changes in mutant phenotypes of neurons. TINS 20: 501–507PubMedGoogle Scholar
  18. Hentze MW, Kulozik AE (1999) A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96: 307–310PubMedCrossRefGoogle Scholar
  19. Hernandez D, Fisher EMC (1996) Down syndrome genetics: unraveling a multifactorial disorder. Hum Mol Genet 5: 1411–1416PubMedGoogle Scholar
  20. Hol EM, Neubauer A, De Kleijn DPV, Sluijs JA, Ramdjielal RDJ, Sonnemans MAF, Van Leeuwen FW (1998a) Dinucleotide deletions in neuronal transcripts: a novel type of mutation in non-familial Alzheimer’s disease and Down syndrome patients. Progr Brain Res 117: 379–394CrossRefGoogle Scholar
  21. Hol EM, Sluijs JA, Sonnemans MAF, Versteeg R, Van Leeuwen FW (1998b) Frameshift mutations in β-amyloid precursor protein and ubiquitin-B RNA in human neuronal cell lines. Abstr Soc Neurosci Meeting 24: 722Google Scholar
  22. Ivell R, Burbach JPH, Van Leeuwen FW (1990) The molecular biology of the Brattleboro rat. Front Neuroendocrinol 11: 313–338Google Scholar
  23. Jacques JP, Kolakofsky D (1991) Pseudo-templated transcription in prokaryotic and eukaryotic organisms. Genes Dev 5: 707–713PubMedCrossRefGoogle Scholar
  24. Jin L-W, Ninomiya H, Roch J-M, Schubert D, Masliah E, Otero DAC, Saitoh T (1994) Peptides containing the RERMS sequence of amyloid β/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci 14: 5461–5470PubMedGoogle Scholar
  25. Kola I, Hertzog PJ (1997) Animal models in the study of the biological function of genes on human chromosome 21 and their role in the pathophysiology of Down syndrome. Hum Mol Genet 6: 1713–1727PubMedCrossRefGoogle Scholar
  26. Kola I, Hertzog PJ (1998) Down syndrome and mouse models. Curr Opin Genet Dev 8: 316–321PubMedCrossRefGoogle Scholar
  27. Kolakofsky D, Hausmann S (1998) Co-transcriptional paramyxovirus mRNA editing; a contradiction in terms? In: Grosjean H, Benne R (eds) Modification and editing of RNA. ASM Press, Washington DC, pp 413–420Google Scholar
  28. Kunkel TA (1995) The intricacies of eukaryotic spell-checking. Curr Biol 5: 1091–1094PubMedCrossRefGoogle Scholar
  29. Lin C-LG, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothestein JD (1998) Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20: 589–602PubMedCrossRefGoogle Scholar
  30. Mann DMA (1997) Molecular biology’s impact on our understanding of aging. BMJ 315: 1078–1081PubMedCrossRefGoogle Scholar
  31. Mann DMA, Prinja D, Davies CA, Iahara Y, Delacourte A, Défossez A, Mayer RJ, Landon M (1989) Immunocytochemical profile of neurofibrillary tangles in Down’s syndrome patients of different ages. J Neurol Sci 92: 247–260PubMedCrossRefGoogle Scholar
  32. Mayer RJ, Arnold J, Lásló L, Landon M, Lowe J (1991) Ubiquitin in health and disease. Biochim Biophys Acta 1089: 141–157PubMedCrossRefGoogle Scholar
  33. Mayer RJ, Tipler C, Arnold J, Lásló L, Al-Khedhairy A, Lowe J, Landon M (1996) Endosome-lysosomes, ubiquitin and neurodegeneration. Adv Exp Med Biol 389: 261–269PubMedCrossRefGoogle Scholar
  34. McPhaul L, Wang J, Yuan SW, French SW, Van Leeuwen FW (1999) Frameshift mutants of ubiquitin-B in Mallory body formation in human liver. FASEB J 13: A736Google Scholar
  35. Mori H, Kondo J, Ihara Y (1987) Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 235: 1641–1644PubMedCrossRefGoogle Scholar
  36. Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Titani K, Ihara Y (1993) Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments. Neuron 10: 1151–1160PubMedCrossRefGoogle Scholar
  37. Neve RL, Finch EA, Dawes LR (1988) Expression of the Alzheimer amyloid precursor gene transcript in the human brain. Neuron 1: 669–677PubMedCrossRefGoogle Scholar
  38. Newman AJ (1994) Pre-mRNA splicing. Curr Opin Gen Dev 4: 298–304CrossRefGoogle Scholar
  39. Ott A, Bretler MMB, Van Harskamp F, Claus JJ, Van der Cammen TJM, Grobbee DE, Hofman A (1995) Prevalence of Alzheimer’s disease and vascular dementia: association with education. The Rotterdam study. Br Med J 310: 970–973CrossRefGoogle Scholar
  40. Palmert MR, Podlisny MB, Witker DS, Oltersdorf T, Younkin LH, Selker DJ, Younkin SG (1998) Antisera to an amino-terminal peptide detect the amyloid precursor of Alzheimer’s disease and recognize senile plaques. Biochem Biophys Res Commun 136: 432–437Google Scholar
  41. Pericak-Vance MA, Bass MP, Ya aoka LH, Gaskell PC, Scott WK, Terwedow HA, Menold MM, Connealy PM, Small GW, Vance JM, Satinders AM, Roses AD, Haines JL (1997) Complete genomic screen in late-onset familial Alzheimer disease. Guidance for a new locus on chromosome 12. JAMA 278: 1237–1241PubMedCrossRefGoogle Scholar
  42. Perlick HA, Medghalchi SM, Spencer FA, Kendzior Jr RJ, Dietz HC (1996) Mammalian orthologues of a yeast regulator of nonsense transcript stability. Proc Natl Acad Sci USA 93: 10928–10932PubMedCrossRefGoogle Scholar
  43. Pulak R, Anderson P (1993) mRNA surveillance by the Caenor habditis elegans Smg genes. Genes Dev 7: 1885–1887PubMedCrossRefGoogle Scholar
  44. Radman M, Wagner R (1988) The high fidelity of DNA duplication. Sci Am August: 24–30Google Scholar
  45. Ruiz-Echevarría MJ, Czaplinski K, Peltz SW (1996) Making sense of nonsense in yeast. Trends Biochem Sci 21: 433–438PubMedCrossRefGoogle Scholar
  46. Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G, Martins R, Hockey A, Montgomery P, Beyreuther K, Masters CL (1989) Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. N Engl J Med 320: 1446–1452PubMedCrossRefGoogle Scholar
  47. Sago H, Carlson EJ, Smith DJ, Kilbridge J, Rubin EM, Mobley WC, Epstein CJ, Huang T-T (1998) TslCje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc Natl Acad Sci USA 95: 6256–6261PubMedCrossRefGoogle Scholar
  48. Schmale H, Borowiak B, Holt-Grez H, Richter D (1989) Impact of altered protein structures on the intracellular traffic of a mutated vasopressin precursor from Brattleboro rats. Eur J Biochem 182: 621–627PubMedCrossRefGoogle Scholar
  49. Sherman TG, Watson SJ (1988) Differential expression of vasopressin alleles in the Brattleboro heterozygote. J Neurosci 8: 3797–3811PubMedGoogle Scholar
  50. Sonnemans MAF, Evans DAP, Burbach JPH, Van Leeuwen FW (1996) Immunocy-tochemical evidence for the presence of vasopressin in intermediate sized neurosecretory granules of solitary neurohypophyseal terminals in the homozygous Brattleboro rat. Neuroscience 72: 225–231PubMedCrossRefGoogle Scholar
  51. Strachan T, Read AP (1996) Human molecular genetics. Bios Scientific Publishers Ltd, OxfordGoogle Scholar
  52. Swaab DF, Lucassen PJ, Salehi A, Scherder EJA, Van Someren EJW, Verwer RWH (1998) Reduced neuronal activity and reactivation in Alzheimer’s disease. Progr Brain Res 117: 343–377CrossRefGoogle Scholar
  53. Szot P, Dorsa DM (1992) Cytoplasmic and nuclear vasopressin RNA in hypothalamic and extrahypothalamic neurons of the Brattleboro rat: an in situ hybridization study. Mol Cell Neurosci 3: 224–236PubMedCrossRefGoogle Scholar
  54. Valtin H (1982) The discovery of the Brattleboro rat, recommended nomenclature, and the question of proper controls. Ann NY Acad Sci 394: 1–9PubMedCrossRefGoogle Scholar
  55. Van Broeckhoven CL (1995) Molecular genetics of Alzheimer disease: identification of genes and gene mutations. Eur Neurol 35: 8–19PubMedCrossRefGoogle Scholar
  56. Van Broeckhoven C (1998) Alzheimer’s disease: identification of genes and genetic risk factor. In: Van Leeuwen FW et al (eds) Neuronal degeneration and regeneration: from basic mechanisms to prospects for therapy. Progr Brain Res 117: 315–326CrossRefGoogle Scholar
  57. Van Duijn CM, De Knijff P, Cruts M, Wehnert A, Havekes LM, Hofman A, Van Broeckhoven C (1994) Apolipoprotein E4 allele in a population-based study of early onset Alzheimer’s disease. Nature Genet 7: 74–78PubMedCrossRefGoogle Scholar
  58. Van Leeuwen FW, Van der Beek EM, Seger M, Burbach JPH, Ivell R (1989) Age-related development of a heterozygous phenotype in solitary neurons of the homozygous Brattleboro rat. Proc Natl Acad Sci USA 86: 6417–6420PubMedCrossRefGoogle Scholar
  59. Van Leeuwen FW, De Kleijn DPV, Van den Hurk HH, Neubauer A, Sonnemans MAF, Sluijs JA, Köycü S, Ramdjielal RDJ, Salehi A, Martens GJM, Grosveld FG, Burbach JPH, Hol EM (1998a) Frameshift mutants of β amyloid precursor protein and ubiquitin-B in Alzheimer’s and Down patients. Science 279: 242–247PubMedCrossRefGoogle Scholar
  60. Van Leeuwen FW, Burbach JPH, Hol EM (1998b) Mutations in RNA: a first example of molecular misreading in Alzheimer’s disease. TINS 21: 331–335PubMedGoogle Scholar
  61. Varshavsky A (1997) The ubiquitin system. Trends Biochem Sci 22: 383–387PubMedCrossRefGoogle Scholar
  62. Vogel G (1998) Possible new cause of Alzheimer’s disease found. Science 279: 174PubMedCrossRefGoogle Scholar
  63. Wiborg O, Pederson MS, Wind A, Berglund LE, Marcker KA, Vuust J (1985) The human ubiquitin multigene family: some genes contain multiple directly repeated ubiquitin coding sequences. EMBO J 4: 755–759PubMedGoogle Scholar
  64. Wisniewski KE, Wisniewski HM, Gy W (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrom. Ann Neurol 17: 278–282PubMedCrossRefGoogle Scholar
  65. 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: 257–263PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1999

Authors and Affiliations

  • F. W. van Leeuwen
    • 1
  • E. M. Hol
    • 1
  1. 1.Netherlands Institute for Brain ResearchAmsterdamThe Netherlands

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