Mutations in RNA: a first example of molecular misreading in Alzheimer's disease

Leeuwen, Fred W. van; Hol, Elly M.; Burbach, Peter H.

doi:10.1016/s0166-2236(98)01280-6

Cited by 97 publications

(90 citation statements)

References 42 publications

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“…2 A, lanes 2 and 3) and the short duration of the experiment (26 h). Our results therefore suggest that Ub ϩ1 -capped chains could accumulate to significant levels in aging brain even though molecular misreading is an inefficient process (17)(18)(19).…”

Section: Assembly Of Ubmentioning

confidence: 76%

“…Recently, van Leeuwen and coworkers (17,18) discovered that a mutant form of Ub, termed Ub ϩ1 , is selectively expressed in the brains of AD patients. Expression of Ub ϩ1 occurs through a phenomenon known as molecular misreading, in which non-DNA-encoded dinucleotide deletion(s) are found in mRNA within or adjacent to GAGAG motifs (17)(18)(19).…”

mentioning

confidence: 99%

“…Expression of Ub ϩ1 occurs through a phenomenon known as molecular misreading, in which non-DNA-encoded dinucleotide deletion(s) are found in mRNA within or adjacent to GAGAG motifs (17)(18)(19). Van Leeuwen et al (17) localized a dinucleotide deletion to the first coding unit of a polyUb transcript, causing replacement of the C-terminal residue of Ub (G76) with a 20-residue (ϩ1) extension.…”

mentioning

confidence: 99%

“…Those investigators used several approaches to show that Ub ϩ1 was present in the brains of AD patients, including those without known predisposing factors (17). In contrast, Ub ϩ1 was present at a significantly reduced level in the brains of nondemented control patients (17,18). Although these results demonstrated a striking correlation between Ub ϩ1 expression and AD pathogenesis, it was unclear why Ub ϩ1 expression should be deleterious.…”

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confidence: 99%

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Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Lam

Pickart

Alban

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

303

213

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Alzheimer's disease is the most common cause of dementia in the elderly. Although several genetic defects have been identified in patients with a family history of this disease, the majority of cases involve individuals with no known genetic predisposition. A mutant form of ubiquitin, termed Ub ؉1 , has been selectively observed in the brains of Alzheimer's patients, including those with nonfamilial Alzheimer's disease, but it has been unclear why Ub ؉1 expression should be deleterious. Here we show that Ub ؉1 is an efficient substrate for polyubiquitination in vitro and in transfected human cells. The resulting polyubiquitin chains are refractory to disassembly by deubiquitinating enzymes and potently inhibit the degradation of a polyubiquitinated substrate by purified 26S proteasomes. Thus, expression of Ub ؉1 in aging brain could result in dominant inhibition of the Ub-proteasome system, leading to neuropathologic consequences.

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Section: Assembly Of Ubmentioning

confidence: 76%

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Lam

Pickart

Alban

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

303

213

View full text Add to dashboard Cite

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“…This information is passed from DNA to RNA and from RNA to protein during gene expression; however, the accuracy of these downstream events is relatively less understood. Although RNA and proteins are generally considered short-lived noninherited molecules, several diseases are now known to arise from errors occurring during transcription and translation (1)(2)(3), implying that faithful transfer of genetic information from DNA to proteins is crucial for maintaining proper cellular functions.…”

mentioning

confidence: 99%

Visualizing high error levels during gene expression in living bacterial cells

Meyerovich

Mamou

Ben-Yehuda

2010

Proc. Natl. Acad. Sci. U.S.A.

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To monitor inaccuracy in gene expression in living cells, we designed an experimental system in the bacterium Bacillus subtilis whereby spontaneous errors can be visualized and quantified at a single-cell level. Our strategy was to introduce mutations into a chromosomally encoded gfp allele, such that errors in protein production are reported in real time by the formation of fluorescent GFP molecules. The data reveal that the amount of errors can greatly exceed previous estimates, and that the error rate increases dramatically at lower temperatures and during stationary phase. Furthermore, we demonstrate that when facing an antibiotic threat, an increase in error level is sufficient to allow survival of bacteria carrying a mutated antibiotic-resistance gene. We propose that bacterial gene expression is error prone, frequently yielding protein molecules that differ slightly from the sequence specified by their DNA, thus generating a cellular reservoir of nonidentical protein molecules. This variation may be a key factor in increasing bacterial fitness, expanding the capability of an isogenic population to face environmental challenges.Bacillus subtilis | translational errors | variations in living cells | translation fidelity D NA is duplicated with remarkable fidelity to ensure that accurate genetic information is transmitted from one generation to the next. This information is passed from DNA to RNA and from RNA to protein during gene expression; however, the accuracy of these downstream events is relatively less understood. Although RNA and proteins are generally considered short-lived noninherited molecules, several diseases are now known to arise from errors occurring during transcription and translation (1-3), implying that faithful transfer of genetic information from DNA to proteins is crucial for maintaining proper cellular functions.

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A unifying hypothesis of Alzheimer's disease. III. Risk factors

Heininger

2000

Hum. Psychopharmacol. Clin. Exp.

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Normal ageing and Alzheimer's disease (AD) have many features in common and, in many respects, both conditions only differ by quantitative criteria. A variety of genetic, medical and environmental factors modulate the ageing-related processes leading the brain into the devastation of AD. In accordance with the concept that AD is a metabolic disease, these risk factors deteriorate the homeostasis of the Ca(2+)-energy-redox triangle and disrupt the cerebral reserve capacity under metabolic stress. The major genetic risk factors (APP and presenilin mutations, Down's syndrome, apolipoprotein E4) are associated with a compromise of the homeostatic triangle. The pathophysiological processes leading to this vulnerability remain elusive at present, while mitochondrial mutations can be plausibly integrated into the metabolic scenario. The metabolic leitmotif is particularly evident with medical risk factors which are associated with an impaired cerebral perfusion, such as cerebrovascular diseases including stroke, cardiovascular diseases, hypo- and hypertension. Traumatic brain injury represents another example due to the persistent metabolic stress following the acute event. Thyroid diseases have detrimental sequela for cerebral metabolism as well. Furthermore, major depression and presumably chronic stress endanger susceptible brain areas mediated by a host of hormonal imbalances, particularly the HPA-axis dysregulation. Sociocultural and lifestyle factors like education, physical activity, diet and smoking may also modulate the individual risk affecting both reserve capacity and vulnerability. The pathophysiological relevance of trace metals, including aluminum and iron, is highly controversial; at any rate, they may adversely affect cellular defences, antioxidant competence in particular. The relative contribution of these factors, however, is as individual as the pattern of the factors. In familial AD, the genetic factors clearly drive the sequence of events. A strong interaction of fat metabolism and apoE polymorphism is suggested by intercultural epidemiological findings. In cultures, less plagued by the 'blessings' of the 'cafeteria diet-sedentary' Western lifestyle, apoE4 appears to be not a risk factor for AD. This intriguing evidence suggests that, analogous to cardiovascular diseases, apoE4 requires a hyperlipidaemic lifestyle to manifest as AD risk factor. Overall, the etiology of AD is a key paradigm for a gene-environment interaction. Copyright 2000 John Wiley & Sons, Ltd.

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Mutations in RNA: a first example of molecular misreading in Alzheimer's disease

Cited by 97 publications

References 42 publications

Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Visualizing high error levels during gene expression in living bacterial cells

A unifying hypothesis of Alzheimer's disease. III. Risk factors

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