Molecular misreading: a new type of transcript mutation expressed during aging

Dinucleotide deletions (e.g. Delta GA, Delta GU) are created by molecular m isreading in or adjacent to GAGAG motifs of neuronal mRNAs. As a result, th e reading frame shifts to the +1 frame, and so-called "+1 proteins" are sub sequently synthesized. +1 Proteins have a wild-type N-terminus, but an aber rant C-terminus downstream from the site of the dinucleotide deletion. Mole cular misreading was discovered in the rat vasopressin gene associated with diabetes insipidus and subsequently in human genes linked to Alzheimer's d isease (AD), e.g. beta amyloid precursor protein (beta APP1 and ubiquitin-B (UBB). Furthermore, beta APP(+1) and UBB+1 proteins accumulate in the neur opathological hallmarks (i.e. in the tangles, neuritic plaques, and neuropi l threads) of AD. As these +1 proteins were also found in elderly nondement ed controls, but not in younger ones (<51 years), molecular misreading in n ondividing cells might act as a factor that only becomes manifest at an adv anced age. Frameshift mutations (UBB-1) and pretangle staining (Alz-50 and MC1) seem to occur independently of each other during early stages of AD. W e recently detected +1 proteins, not only in proliferating cells present in non-neuronal tissues such as the liver and epididymis, but also in neurobl astoma cell lines. These observations suggest that molecular misreading is a general source of transcript errors that are involved in cellular derange ments in various age-related pathologies. (C) 2000 Elsevier Science Inc. Al l rights reserved.