Molecular misreading of genes in Down syndrome as a model for the Alzheimer type of neurodegeneration
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.
KeywordsDown Syndrome Paired Helical Filament Down Syndrome Patient Neuropil Thread mRNA Surveillance
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- 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
- Finch CE (1990) Longevity, senescence and the genome. University of Chicago Press, ChicagoGoogle Scholar
- 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
- Ivell R, Burbach JPH, Van Leeuwen FW (1990) The molecular biology of the Brattleboro rat. Front Neuroendocrinol 11: 313–338Google Scholar
- 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
- 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
- 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
- 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
- Radman M, Wagner R (1988) The high fidelity of DNA duplication. Sci Am August: 24–30Google Scholar
- Strachan T, Read AP (1996) Human molecular genetics. Bios Scientific Publishers Ltd, OxfordGoogle Scholar
- 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