Early detection of PrP res in BSE-infected bovine PrP transgenic mice

Castilla, Joaquı́n; Adan, Aysun; Brun, Alejandro; Pintado, Belén; Ramírez, Miguel Ángel; Parra, Beatriz; Doyle, Deirdre; Rogers, Mark; Salguero, Francisco J.; Sánchez, Carlos Manuel Fernández; Sánchez-Vizcaíno, José Manuel; Torres, Juan María

doi:10.1007/s00705-002-0958-4

Cited by 118 publications

(66 citation statements)

References 25 publications

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“…All but the bovine PrP expressing mice (tgBov) were established on the same mouse PrP Ko background (Zurich I) [28]–[30]. In each of these mouse lines relative PrP expression level in the brain, by comparison to the natural host species, was described (tga20: 10-fold–tg338: 6–8 fold, tgBov/tg110: 8-fold, tgShpXI: 3–4-fold, tg650: 6-fold) [28], [31]–[34] …”

Section: Methodsmentioning

confidence: 99%

Preclinical Detection of Variant CJD and BSE Prions in Blood

et al. 2014

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The emergence of variant Creutzfeldt Jakob Disease (vCJD) is considered a likely consequence of human dietary exposure to Bovine Spongiform Encephalopathy (BSE) agent. More recently, secondary vCJD cases were identified in patients transfused with blood products prepared from apparently healthy donors who later went on to develop the disease. As there is no validated assay for detection of vCJD/BSE infected individuals the prevalence of the disease in the population remains uncertain. In that context, the risk of vCJD blood borne transmission is considered as a serious concern by health authorities. In this study, appropriate conditions and substrates for highly efficient and specific in vitro amplification of vCJD/BSE agent using Protein Misfolding Cyclic Amplification (PMCA) were first identified. This showed that whatever the origin (species) of the vCJD/BSE agent, the ovine Q171 PrP substrates provided the best amplification performances. These results indicate that the homology of PrP amino-acid sequence between the seed and the substrate is not the crucial determinant of the vCJD agent propagation in vitro. The ability of this method to detect endogenous vCJD/BSE agent in the blood was then defined. In both sheep and primate models of the disease, the assay enabled the identification of infected individuals in the early preclinical stage of the incubation period. Finally, sample panels that included buffy coat from vCJD affected patients and healthy controls were tested blind. The assay identified three out of the four tested vCJD affected patients and no false positive was observed in 141 healthy controls. The negative results observed in one of the tested vCJD cases concurs with results reported by others using a different vCJD agent blood detection assay and raises the question of the potential absence of prionemia in certain patients.

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Section: Methodsmentioning

confidence: 99%

Preclinical Detection of Variant CJD and BSE Prions in Blood

et al. 2014

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“…This line is homozygous and exhibits approximately 6-fold overexpression of human PrP C (Met 129 allele) in the brain. The bovine PrP tg110 line has been described previously (25).…”

Section: Ethics Statementmentioning

confidence: 99%

Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice

Jaumain

Quadrio

Herzog

et al. 2016

J Virol

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Prions are proteinaceous pathogens responsible for subacute spongiform encephalopathies in animals and humans. The prions responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents, causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of prions between species is limited by a species barrier, which is thought to reflect structural incompatibilities between the host cellular prion protein (PrP C ) and the infecting pathological PrP assemblies (PrP Sc ) constituting the prion. A BSE strain variant, designated L-BSE and responsible for atypical, supposedly spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic potential, as evidenced by its capacity to propagate more easily than classical BSE in transgenic mice expressing human PrP C and in nonhuman primates. In humanized mice, L-BSE propagates without any apparent species barrier and shares similar biochemical PrP Sc signatures with the CJD subtype designated MM2-cortical, thus opening the possibility that certain CJD cases classified as sporadic may actually originate from L-type BSE cross-transmission. To address this issue, we compared the biological properties of L-BSE and those of a panel of CJD subtypes representative of the human prion strain diversity using standard strain-typing criteria in human PrP transgenic mice. We found no evidence that L-BSE causes a known form of sporadic CJD. IMPORTANCESince the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population. P rions are pathogens formed from abnormally folded assemblies (PrP Sc ) of the host-encoded prion protein PrP C . Upon infection, they self-replicate by converting host PrP C into PrP Sc assemblies (1). Within defined host species, PrP C can transconform into multiple strains differing in their PrP Sc conformations and in their biological properties in tissues from reporter animals or in cell lines (2-6).In humans, prions can form sporadically and induce Creutzfeldt-Jakob disease (CJD), mainly in elderly people. The worldwide incidence of sporadic CJD (sCJD) ranges from one to two cases per million people per year (7). Evaluation of both the PrP Sc electrophoretic pattern after proteinase K treatment and the methionine/valine polymorphism at codon 129 of the gene encoding PrP allows the definition of multiple sCJD molecular subtypes, which exhibit specific clinical and neuropathological features (8-10). The most common form of sCJD is associated with the presence of type 1 (T1) protease-resistant PrP Sc (PrP res ) and methionine homozygosity (MM) at codon 129. Rare forms of MM sporadic CJD with a type 2 (T2) PrP r...

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“…It can also be found, but at lower levels, in neuroglia, the reproductive tract, spleen, lymph nodes, and immune cells (Brown et al 2000, Ford et al 2002. Its role in prion diseases has been well described, wherein a conformational isoform of this protein (PrP Sc ) could lead to the appearance of typical pathognomonic symptoms (Prusiner 1982, Castilla et al 2003. The first knockout (KO) mouse models were generated in the 1990s (Bueler et al 1992, Manson et al 1994, which helped to demonstrate that PrP C is essential in these neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

The role of prion protein in stem cell regulation

Miranda¹,

Ramos‐Ibeas

Pericuesta

et al. 2013

Reproduction

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Cellular prion protein (PrP C ) has been well described as an essential partner of prion diseases due to the existence of a pathological conformation (PrP Sc ). Recently, it has also been demonstrated that PrP C is an important element of the pluripotency and self-renewal matrix, with an increasing amount of evidence pointing in this direction. Here, we review the data that demonstrate its role in the transcriptional regulation of pluripotency, in the differentiation of stem cells into different lineages (e.g. muscle and neurons), in embryonic development, and its involvement in reproductive cells. Also highlighted are recent results from our laboratory that describe an important regulation by PrP C of the major pluripotency gene Nanog. Together, these data support the appearance of new strategies to control stemness, which could represent an important advance in the field of regenerative medicine.Reproduction (2013) 146 R91-R99

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Early detection of PrP res in BSE-infected bovine PrP transgenic mice

Cited by 118 publications

References 25 publications

Preclinical Detection of Variant CJD and BSE Prions in Blood

Preclinical Detection of Variant CJD and BSE Prions in Blood

Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice

The role of prion protein in stem cell regulation

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