QoSOS: An Adaptable Architecture for QoS Provisioning in Network Operating Systems

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Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrP Sc ). The normal, cellular PrP (PrP C ) is converted into PrP Sc through a posttranslational process during which it acquires a high ␤-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrP Sc . Transgenetic studies argue that PrP Sc acts as a template upon which PrP C is refolded into a nascent PrP Sc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrP Sc . While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

mentioning

confidence: 76%

“…The prototypic strains called Me7 and 22A gave incubation times of Ϸ150 and Ϸ400 days in C57BL mice, respectively (215, 268, 269). The PrP genes of C57BL and I͞Ln (and later VM) mice encode proteins differing at two residues and control scrapie incubation times (195,213,(217)(218)(219)270).…”

mentioning

confidence: 99%

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

Chisholm

Dahlbeck

Krishnamurthy

et al. 2005

137

138

“…Ablation of the Prnp gene renders mice unable to replicate murine-adapted scrapie strains (7), and increasing PrP overexpression levels in transgenic mice generally reduces the incubation time (8,9). Allelic forms of PrP have been linked to the disease susceptibility in several species including mice (10), sheep (11), and humans (12,13). The genetic linkage between familial TSEs and mutations in the human Prnp gene (14) also exemplifies the crucial role of PrP in TSEs.…”

mentioning

confidence: 99%

Ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein

Vilette

Andréoletti

Archer

et al. 2001

199

263

Transmissible spongiform encephalopathies, or prion diseases, are fatal degenerative disorders of the central nervous system that affect humans and animals. Prions are nonconventional infectious agents whose replication depends on the host prion protein (PrP). Transmission of prions to cultured cells has proved to be a particularly difficult task, and with a few exceptions, their experimental propagation relies on inoculation to laboratory animals. Here, we report on the development of a permanent cell line supporting propagation of natural sheep scrapie. This model was obtained by stable expression of a tetracycline-regulatable ovine PrP gene in a rabbit epithelial cell line. After exposure to scrapie agent, cultures were repeatedly found to accumulate high levels of abnormal PrP (PrPres). Cell extracts induced a scrapie-like disease in transgenic mice overexpressing ovine PrP. These cultures remained healthy and stably infected upon subpassaging. Such data show that (i) cultivated cells from a nonneuronal origin can efficiently replicate prions; and (ii) species barrier can be crossed ex vivo through the expression of a relevant PrP gene. This approach led to the ex vivo propagation of a natural transmissible spongiform encephalopathy agent (i.e., without previous experimental adaptation to rodents) and might be applied to human or bovine prions.

“…All cases of vCJD described to date have occurred in methionine homozygous individuals, a genotype shared by Ϸ40% of the British Caucasian population (10). In mice, two polymorphisms in the murine PrP gene (Prnp) have been described where Prnp a (Leu-108, Thr-189) and Prnp b (Phe-108, Val-189) are associated with short and long incubation times, respectively (6,(11)(12)(13).…”

mentioning

confidence: 99%

Identification of multiple quantitative trait loci linked to prion disease incubation period in mice

Lloyd

Onwuazor

Beck

et al. 2001

172

153

Polymorphisms in the prion protein gene are known to affect prion disease incubation times and susceptibility in humans and mice. However, studies with inbred lines of mice show that large differences in incubation times occur even with the same amino acid sequence of the prion protein, suggesting that other genes may contribute to the observed variation. To identify these loci we analyzed 1,009 animals from an F2 intercross between two strains of mice, CAST͞Ei and NZW͞OlaHSd, with significantly different incubation periods when challenged with RML scrapie prions. Interval mapping identified three highly significantly linked regions on chromosomes 2, 11, and 12; composite interval mapping suggests that each of these regions includes multiple linked quantitative trait loci. Suggestive evidence for linkage was obtained on chromosomes 6 and 7. The sequence conservation between the mouse and human genome suggests that identification of mouse prion susceptibility alleles may have direct relevance to understanding human susceptibility to bovine spongiform encephalopathy (BSE) infection, as well as identifying key factors in the molecular pathways of prion pathogenesis. However, the demonstration of other major genetic effects on incubation period suggests the need for extreme caution in interpreting estimates of variant Creutzfeldt-Jakob disease epidemic size utilizing existing epidemiological models.