Molecular misreading is a novel process that causes mutations
in neuronal transcripts.
1 It is defined as the inaccurate conversion
of genomic information from DNA into nonsense transcripts and
the subsequent translation into mutant proteins.
2 As a result
of dinucleotide deletions (
GA,
GU,
CU) in and around GAGAG motifs
in mRNA the reading frame shifts to the +1 rame, and subsequently
the so-called +1 proteins are synthetized. +1 Proteins have
a wild-type NH2 terminus and from the site of the dinucleotide
deletion onwards an aberrant, nonfunctional COOH terminus. Molecular
misreading was found in the rat vasopressin gene associated
with diabetes insipidus
3 and in the human genes linked to Alzheimer's
disease (AD), that is, ß-amyloid precursor protein
(ßAPP) and ubiquitin-B (UBB).
1,2 Moreover, ßAPP
+1 and UBB+1 proteins accumulate in the neuropathological hallmarks
of AD. Inasmuch as these +1 proteins were also found in elderly,
nondemented control patients, but not in younger ones (<72
years), molecular misreading may act as a factor that becomes
manifest in aged people. A hotspot for dinucleotide deletions
is GAGAG motifs. Because statistically an average of 2.1 GAGAG
motifs per gene can be expected, other genes expressed in other
tissues may undergo molecular misreading as well. Indeed, we
recently detected +1 proteins in proliferating cells present
in tissues such as the liver, epididymis, parotid gland, and
neuroblastoma cell lines.
4 Therefore, molecular misreading
can be regarded as a general biological source of transcript
errors that may be involved in cellular derangements in numerous
age-related pathologic conditions apart from Alzheimer's disease.
