Molecular misreading: the frequency of dinucleotide deletions in neuronal mRNAs for beta-amyloid precursor protein and ubiquitin B

Lisya Gerez, Annett de Haan, Elly M Hol, David F Fischer, Fred W van Leeuwen, Harry van Steeg, Rob Benne

Research output: Contribution to journalArticleAcademicpeer-review


Human neuronal cells contain mutant beta-amyloid precursor protein (APP) and ubiquitin B (UBB) mRNAs, in which dinucleotide deletions ('Delta') are generated in/around GAGAG-motifs by an unknown mechanism referred to as 'Molecular Misreading.' The encoded frameshifted (+1) proteins accumulate in the neuropathological hallmarks of Alzheimer's disease (AD) and in other neurodegenerative and age-related diseases. To measure the concentration of Delta mRNAs, we developed a highly sensitive and specific assay, utilizing peptide nucleic acid-mediated PCR clamping, followed by cloning and colony hybridization with sequence-specific oligonucleotide probes. We found only a few molecules of Delta mRNA/microg of cellular RNA, at levels <10(-5) to 10(-6) x the concentration of WT mRNA, in RNA extracted from: (i) cultured human neuroblastoma cells grown under a variety of conditions, (ii) the frontal half of brains from wild type and XPA(-/-) DNA repair-deficient mice, and (iii) post-mortem temporal cortices from humans. Importantly, in RNA from the temporal cortices of AD and Down Syndrome patients that contain betaAPP+1 and UBB+1 immunoreactive cells, we found the same low levels of Delta mRNA. We infer that the accumulation of +1 proteins in neurons of these patients is not caused by an increase in the concentration of Delta mRNAs.

Original languageEnglish
Pages (from-to)145-55
Number of pages11
JournalNeurobiology of Aging
Issue number2
Publication statusPublished - Feb 2005


  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease
  • Amyloid beta-Protein Precursor
  • Animals
  • Brain
  • Cell Line
  • DNA-Binding Proteins
  • Dinucleoside Phosphates
  • Down Syndrome
  • Electrophoresis
  • Female
  • Gene Deletion
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Molecular Biology
  • Neurons
  • Nucleic Acid Hybridization
  • Postmortem Changes
  • RNA, Messenger
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquitin
  • Xeroderma Pigmentosum Group A Protein
  • Comparative Study
  • Journal Article
  • Research Support, Non-U.S. Gov't


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