Abstract
In patients with Alzheimer's disease or Down's syndrome, the cerebellar cortex exhibits protein deposits in neurofibrillary tangles and neuritic plaques. Recently, the deposits have been shown to contain protein fragments of ubiquitin-B and amyloid precursor protein (APP) with an aberrant carboxyl terminus resulting from frameshift mutations (dinucleotide deletions; DeltaGU or DeltaGA) in or adjacent to GAGAG motifs in their mRNAs, a process referred to as molecular misreading. We have now used a bacterial expression system with the green fluorescent protein as a reporter to screen gene transcripts from aged controls, Alzheimer's disease, and Down's syndrome for molecular misreading. Novel frameshift mutations at a number of locations in the transcripts of the ubiquitin-B and APP genes were discovered (DeltaGA, DeltaG, DeltaGU, DeltaGG, DeltaCA, DeltaAU, DeltaA, DeltaAA, DeltaC, DeltaU, and insertion of an A). Interestingly, most mutations were in close proximity of short simple repeats (GAGAG, GGUGGU, GAGACACACA, UCAUCAUCA, CAAACAAA, and GAAGAAGAA), demonstrating that the GAGAG motif does not constitute the only hot spot for transcriptional errors. Unlike the previously detected aberrant APP fragments, some of the novel ones have the potential to generate the neurotoxic peptide beta-amyloid. We conclude that during aging molecular misreading is a widespread phenomenon.
Highlights
Alzheimer’s disease (AD)1 is a neurodegenerative disorder of the brain and accounts for the most frequent form of dementia at higher age
The deposits have been shown to contain protein fragments of ubiquitin-B and amyloid precursor protein (APP) with an aberrant carboxyl terminus resulting from frameshift mutations in or adjacent to GAGAG motifs in their mRNAs, a process referred to as molecular misreading
Age-related frameshift mutations in gene transcripts have been shown to occur in Brattleboro rats [5] and in patients who had suffered from AD or Down’s syndrome (DS) [2]
Summary
Alzheimer’s disease (AD)1 is a neurodegenerative disorder of the brain and accounts for the most frequent form of dementia at higher age. The deposits have been shown to contain protein fragments of ubiquitin-B and amyloid precursor protein (APP) with an aberrant carboxyl terminus resulting from frameshift mutations (dinucleotide deletions; ⌬GU or ⌬GA) in or adjacent to GAGAG motifs in their mRNAs, a process referred to as molecular misreading.
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