Molecular misreading: a new type of transcript mutation expressed during aging.
Dinucleotide deletions (e.g. DeltaGA, DeltaGU) are created by molecular misreading in or adjacent to GAGAG motifs of neuronal mRNAs. As a result, the reading frame shifts to the +1 frame, and so-called "+1 proteins" are subsequently synthesized. +1 Proteins have a wild-type N-terminus, but an aberrant C-terminus downstream from the site of the dinucleotide deletion. Molecular misreading was discovered in the rat vasopressin gene associated with diabetes insipidus and subsequently in human genes linked to Alzheimer's disease (AD), e.g. beta amyloid precursor protein (betaAPP) and ubiquitin-B (UBB). Furthermore, betaAPP(+1) and UBB(+1) proteins accumulate in the neuropathological hallmarks (i.e. in the tangles, neuritic plaques, and neuropil threads) of AD. As these +1 proteins were also found in elderly nondemented controls, but not in younger ones (<51 years), molecular misreading in nondividing cells might act as a factor that only becomes manifest at an advanced age. Frameshift mutations (UBB(+1)) and pretangle staining (Alz-50 and MC1) seem to occur independently of each other during early stages of AD. We recently detected +1 proteins, not only in proliferating cells present in non-neuronal tissues such as the liver and epididymis, but also in neuroblastoma cell lines. These observations suggest that molecular misreading is a general source of transcript errors that are involved in cellular derangements in various age-related pathologies.
van Leeuwen
F W
FW
Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ, Amsterdam, The Netherlands.
Fischer
D F
DF
Kamel
D
D
Sluijs
J A
JA
Sonnemans
M A
MA
Benne
R
R
Swaab
D F
DF
Salehi
A
A
Hol
E M
EM
D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D003919:Diabetes Insipidus / Q000235:genetics; D016368:Frameshift Mutation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017384:Sequence Deletion; D014158:Transcription, Genetic
D016564:Amyloid beta-Protein Precursor; D012333:RNA, Messenger