Publications by authors named "Vincent Béringue"

94 Publications

Anti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation.

Neurotherapeutics 2021 Feb 2. Epub 2021 Feb 2.

Inserm, Univ Brest, EFS, UMR 1078, GGB, F-29200, Brest, France.

Prion diseases are caused by the propagation of PrP, the pathological conformation of the PrP prion protein. The molecular mechanisms underlying PrP propagation are still unsolved and no therapeutic solution is currently available. We thus sought to identify new anti-prion molecules and found that flunarizine inhibited PrP propagation in cell culture and significantly prolonged survival of prion-infected mice. Using an in silico therapeutic repositioning approach based on similarities with flunarizine chemical structure, we tested azelastine, duloxetine, ebastine, loperamide and metixene and showed that they all have an anti-prion activity. Like flunarizine, these marketed drugs reduced PrP propagation in cell culture and in mouse cerebellum organotypic slice culture, and inhibited the protein folding activity of the ribosome (PFAR). Strikingly, some of these drugs were also able to alleviate phenotypes due to PABPN1 nuclear aggregation in cell and Drosophila models of oculopharyngeal muscular dystrophy (OPMD). These data emphasize the therapeutic potential of anti-PFAR drugs for neurodegenerative and neuromuscular proteinopathies.
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http://dx.doi.org/10.1007/s13311-020-00992-6DOI Listing
February 2021

Michel Brémont (1953-2020).

Vet Res 2020 Dec 30;51(1):146. Epub 2020 Dec 30.

Université Paris-Saclay, INRAE, UVSQ, Jouy-en-Josas, VIM, France.

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http://dx.doi.org/10.1186/s13567-020-00878-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772907PMC
December 2020

Improving the Predictive Value of Prion Inactivation Validation Methods to Minimize the Risks of Iatrogenic Transmission With Medical Instruments.

Front Bioeng Biotechnol 2020 1;8:591024. Epub 2020 Dec 1.

Université Paris Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France.

Prions are pathogenic infectious agents responsible for fatal, incurable neurodegenerative diseases in animals and humans. Prions are composed exclusively of an aggregated and misfolded form (PrP ) of the cellular prion protein (PrP). During the propagation of the disease, PrP recruits and misfolds PrP into further PrP. In human, iatrogenic prion transmission has occurred with incompletely sterilized medical material because of the unusual resistance of prions to inactivation. Most commercial prion disinfectants validated against the historical, well-characterized laboratory strain of 263K hamster prions were recently shown to be ineffective against variant Creutzfeldt-Jakob disease human prions. These observations and previous reports support the view that any inactivation method must be validated against the prions for which they are intended to be used. Strain-specific variations in PrP physico-chemical properties and conformation are likely to explain the strain-specific efficacy of inactivation methods. Animal bioassays have long been used as gold standards to validate prion inactivation methods, by measuring reduction of prion infectivity. Cell-free assays such as the real-time quaking-induced conversion (RT-QuIC) assay and the protein misfolding cyclic amplification (PMCA) assay have emerged as attractive alternatives. They exploit the seeding capacities of PrP to exponentially amplify minute amounts of prions in biospecimens. European and certain national medicine agencies recently implemented their guidelines for prion inactivation of non-disposable medical material; they encourage or request the use of human prions and cell-free assays to improve the predictive value of the validation methods. In this review, we discuss the methodological and technical issues regarding the choice of (i) the cell-free assay, (ii) the human prion strain type, (iii) the prion-containing biological material. We also introduce a new optimized substrate for high-throughput PMCA amplification of human prions bound on steel wires, as translational model for prion-contaminated instruments.
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http://dx.doi.org/10.3389/fbioe.2020.591024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736614PMC
December 2020

PiQSARS: A pipeline for quantitative and statistical analyses of ratiometric fluorescent biosensors.

MethodsX 2020 26;7:101034. Epub 2020 Aug 26.

Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-Yvette, France.

Genetically encoded ratiometric fluorescent probes are cutting-edge tools in biology. They allow precise and dynamic measurement of various physiological parameters within cell compartments. Because data extraction and analysis are time consuming and may lead to inconsistencies between results, we describe here a standardized pipeline for•Semi-automated treatment of time-lapse fluorescence microscopy images.•Quantification of individual cell signal.•Statistical analysis of the data.First, a dedicated macro was developed using the FIJI software to reproducibly quantify the fluorescence ratio as a function of time. Raw data are then exported and analyzed using R and MATLAB softwares. Calculation and statistical analysis of selected graphic parameters are performed. In addition, a functional principal component analysis allows summarizing the dataset. Finally, a principal component analysis is performed to check consistency and final analysis is presented as a visual diagram. The method is adapted to any ratiometric fluorescent probe. As an example, the analysis of the cytoplasmic HyPer probe in response to an acute cell treatment with increasing amounts of hydrogen peroxide is shown. In conclusion, the pipeline allows to save time and analyze a larger amount of samples while reducing manual interventions and consequently increasing the robustness of the analysis.
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http://dx.doi.org/10.1016/j.mex.2020.101034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486618PMC
August 2020

A seven-residue deletion in PrP leads to generation of a spontaneous prion formed from C-terminal C1 fragment of PrP.

J Biol Chem 2020 10 11;295(41):14025-14039. Epub 2020 Aug 11.

Université Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Université de Versailles Saint-Quentin-en-Yvelines, Virologie et Immunologie Moléculaires, Jouy-en-Josas, France

Prions result from a drastic conformational change of the host-encoded cellular prion protein (PrP), leading to the formation of β-sheet-rich, insoluble, and protease-resistant self-replicating assemblies (PrP). The cellular and molecular mechanisms involved in spontaneous prion formation in sporadic and inherited human prion diseases or equivalent animal diseases are poorly understood, in part because cell models of spontaneously forming prions are currently lacking. Here, extending studies on the role of the H2 α-helix C terminus of PrP, we found that deletion of the highly conserved HTVTTTT segment of ovine PrP led to spontaneous prion formation in the RK13 rabbit kidney cell model. On long-term passage, the mutant cells stably produced proteinase K (PK)-resistant, insoluble, and aggregated assemblies that were infectious for naïve cells expressing either the mutant protein or other PrPs with slightly different deletions in the same area. The electrophoretic pattern of the PK-resistant core of the spontaneous prion (Δ) contained mainly C-terminal polypeptides akin to C1, the cell-surface anchored C-terminal moiety of PrP generated by natural cellular processing. RK13 cells expressing solely the Δ190-196 C1 PrP construct, in the absence of the full-length protein, were susceptible to Δ prions. Δ infection induced the conversion of the mutated C1 into a PK-resistant and infectious form perpetuating the biochemical characteristics of Δ prion. In conclusion, this work provides a unique cell-derived system generating spontaneous prions and provides evidence that the 113 C-terminal residues of PrP are sufficient for a self-propagating prion entity.
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http://dx.doi.org/10.1074/jbc.RA120.014738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549040PMC
October 2020

Conformation-dependent membrane permeabilization by neurotoxic PrP oligomers: The role of the H2H3 oligomerization domain.

Arch Biochem Biophys 2020 10 30;692:108517. Epub 2020 Jul 30.

UR892, Virologie et Immunologie Moléculaires, Institut National de la Recherche Agronomique (INRA), Jouy-en-Josas, France; Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR8233, MONARIS, Université Pierre et Marie Curie, Paris, France. Electronic address:

The relationship between prion propagation and the generation of neurotoxic species and clinical onset remains unclear. Several converging lines of evidence suggest that interactions with lipids promote various precursors to form aggregation-prone states that are involved in amyloid fibrils. Here, we compared the cytotoxicities of different soluble isolated oligomeric constructs from murine full-length PrP and from the restricted helical H2H3 domain with their effects on lipid vesicles. The helical H2H3 domain is suggested to be the minimal region of PrP involved in the oligomerization process. The discrete PrP oligomers of both the full-length sequence and the H2H3 domain have de novo β-sheeted structure when interacting with the membrane. They were shown to permeabilize synthetic negatively charged vesicles in a dose-dependent manner. Restricting the polymerization domain of the full-length PrP to the H2H3 helices strongly diminished the ability of the corresponding oligomers to associate with the lipid vesicles. Furthermore, the membrane impairment mechanism occurs differently for the full-length PrP oligomers and the H2H3 helices, as shown by dye-release and black lipid membrane experiments. The membrane damage caused by the full-length PrP oligomers is correlated to their neuronal toxicity at submicromolar concentrations, as shown by cell culture assays. Although oligomers of synthetic H2H3 could compromise in vitro cell homeostasis, they followed a membrane-disruptive pattern that was different from the full-length oligomers, as revealed by the role of PrP in cell viability assays.
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http://dx.doi.org/10.1016/j.abb.2020.108517DOI Listing
October 2020

Host prion protein expression levels impact prion tropism for the spleen.

PLoS Pathog 2020 07 23;16(7):e1008283. Epub 2020 Jul 23.

Université Paris-Saclay, INRAE, UVSQ, VIM Jouy-en-Josas, France.

Prions are pathogens formed from abnormal conformers (PrPSc) of the host-encoded cellular prion protein (PrPC). PrPSc conformation to disease phenotype relationships extensively vary among prion strains. In particular, prions exhibit a strain-dependent tropism for lymphoid tissues. Prions can be composed of several substrain components. There is evidence that these substrains can propagate in distinct tissues (e.g. brain and spleen) of a single individual, providing an experimental paradigm to study the cause of prion tissue selectivity. Previously, we showed that PrPC expression levels feature in prion substrain selection in the brain. Transmission of sheep scrapie isolates (termed LAN) to multiple lines of transgenic mice expressing varying levels of ovine PrPC in their brains resulted in the phenotypic expression of the dominant sheep substrain in mice expressing near physiological PrPC levels, whereas a minor substrain replicated preferentially on high expresser mice. Considering that PrPC expression levels are markedly decreased in the spleen compared to the brain, we interrogate whether spleen PrPC dosage could drive prion selectivity. The outcome of the transmission of a large cohort of LAN isolates in the spleen from high expresser mice correlated with the replication rate dependency on PrPC amount. There was a prominent spleen colonization by the substrain preferentially replicating on low expresser mice and a relative incapacity of the substrain with higher-PrPC level need to propagate in the spleen. Early colonization of the spleen after intraperitoneal inoculation allowed neuropathological expression of the lymphoid substrain. In addition, a pair of substrain variants resulting from the adaptation of human prions to ovine high expresser mice, and exhibiting differing brain versus spleen tropism, showed different tropism on transmission to low expresser mice, with the lymphoid substrain colonizing the brain. Overall, these data suggest that PrPC expression levels are instrumental in prion lymphotropism.
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http://dx.doi.org/10.1371/journal.ppat.1008283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402522PMC
July 2020

Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures.

mBio 2020 06 16;11(3). Epub 2020 Jun 16.

UMR INRA ENVT 1225, Interactions Hôte Agent Pathogène, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France

Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the gene and the proteinase K-digested abnormal prion protein (PrP) isoform identified by Western blotting (type 1 or type 2). Converging evidence led to the view that MM/MV1, VV/MV2, and VV1 and MM2 sCJD cases are caused by distinct prion strains. However, in a significant proportion of sCJD patients, both type 1 and type 2 PrP were reported to accumulate in the brain, which raised questions about the diversity of sCJD prion strains and the coexistence of two prion strains in the same patient. In this study, a panel of sCJD brain isolates ( = 29) that displayed either a single or mixed type 1/type 2 PrP were transmitted into human-PrP-expressing mice (tgHu). These bioassays demonstrated that two distinct prion strains (M1 and V2) were associated with the development of sCJD in MM1/MV1 and VV2/MV2 patients. However, in about 35% of the investigated VV and MV cases, transmission results were consistent with the presence of both M1 and V2 strains, including in patients who displayed a "pure" type 1 or type 2 PrP The use of a highly sensitive prion amplification technique that specifically probes the V2 strain revealed the presence of the V2 prion in more than 80% of the investigated isolates, including isolates that propagated as a pure M1 strain in tgHu. These results demonstrate that at least two sCJD prion strains can be present in a single patient. sCJD occurrence is currently assumed to result from spontaneous and stochastic formation of a misfolded PrP nucleus in the brains of affected patients. This original nucleus then recruits and converts nascent PrP into PrP, leading to the propagation of prions in the patient's brain. Our study demonstrates the coexistence of two prion strains in the brains of a majority of the 23 sCJD patients investigated. The relative proportion of these sCJD strains varied both between patients and between brain areas in a single patient. These findings strongly support the view that the replication of an sCJD prion strain in the brain of a patient can result in the propagation of different prion strain subpopulations. Beyond its conceptual importance for our understanding of prion strain properties and evolution, the sCJD strain mixture phenomenon and its frequency among patients have important implications for the development of therapeutic strategies for prion diseases.
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http://dx.doi.org/10.1128/mBio.00393-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298703PMC
June 2020

The Prion-like protein Shadoo is involved in mouse embryonic and mammary development and differentiation.

Sci Rep 2020 04 21;10(1):6765. Epub 2020 Apr 21.

Université Paris-Saclay, INRAE, AgroParisTech, UMR1313-GABI, 78350, Jouy-en-Josas, France.

Shadoo belongs to the prion protein family, an evolutionary conserved and extensively studied family due to the implication of PrP in Transmissible Spongiform Encephalopathies. However, the biological function of these genes remains poorly understood. While Sprn-knockdown experiments suggested an involvement of Shadoo during mouse embryonic development, Sprn-knockout experiments in 129Pas/C57BL/6J or 129Pas/FVB/NCr mice did not confirm it. In the present study, we analyzed the impact of Sprn gene invalidation in a pure FVB/NJ genetic background, using a zinc finger nuclease approach. The in-depth analysis of the derived knockout transgenic mice revealed a significant increase in embryonic lethality at early post-implantation stages, a growth retardation of young Sprn-knockout pups fed by wild type mice and a lactation defect of Sprn-knockout females. Histological and transcriptional analyses of knockout E7.5 embryos, E14.5 placentas and G7.5 mammary glands revealed specific roles of the Shadoo protein in mouse early embryogenesis, tissue development and differentiation with a potential antagonist action between PrP and Shadoo. This study thus highlights the entanglement between the proteins of the prion family.
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http://dx.doi.org/10.1038/s41598-020-63805-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174383PMC
April 2020

Crossing Species Barriers Relies on Structurally Distinct Prion Assemblies and Their Complementation.

Mol Neurobiol 2020 Jun 1;57(6):2572-2587. Epub 2020 Apr 1.

Université Paris-Saclay, INRAE, UVSQ, VIM, 78350, Jouy-en-Josas, France.

Prion replication results from the autocatalytic templated assisted conversion of the host-encoded prion protein PrP into misfolded, polydisperse PrP conformers. Structurally distinct PrP conformers can give rise to multiple prion strains. Within and between prion strains, the biological activity (replicative efficacy and specific infectivity) of PrP assemblies is size dependent and thus reflects an intrinsic structural heterogeneity. The contribution of such PrP heterogeneity across species prion adaptation, which is believed to be based on fit adjustment between PrP template(s) and host PrP, has not been explored. To define the structural-to-fitness PrP landscape, we measured the relative capacity of size-fractionated PrP assemblies from different prion strains to cross mounting species barriers in transgenic mice expressing foreign PrP. In the absence of a transmission barrier, the relative efficacy of the isolated PrP assemblies to induce the disease is like the efficacy observed in the homotypic context. However, in the presence of a transmission barrier, size fractionation overtly delays and even abrogates prion pathogenesis in both the brain and spleen tissues, independently of the infectivity load of the isolated assemblies. Altering by serial dilution PrP assembly content of non-fractionated inocula aberrantly reduces their specific infectivity, solely in the presence of a transmission barrier. This suggests that synergy between structurally distinct PrP assemblies in the inoculum is requested for crossing the species barrier. Our data support a mechanism whereby overcoming prion species barrier requires complementation between structurally distinct PrP assemblies. This work provides key insight into the "quasispecies" concept applied to prions, which would not necessarily rely on prion substrains as constituent but on structural PrP heterogeneity within prion population.
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http://dx.doi.org/10.1007/s12035-020-01897-3DOI Listing
June 2020

Mixtures of prion substrains in natural scrapie cases revealed by ovinised murine models.

Sci Rep 2020 03 19;10(1):5042. Epub 2020 Mar 19.

Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Facultad de Veterinaria, Instituto Agroalimentario de Aragón - IA2 (Universidad de Zaragoza - CITA), 50013, Zaragoza, Spain.

Phenotypic variability in prion diseases, such as scrapie, is associated to the existence of prion strains, which are different pathogenic prion protein (PrP) conformations with distinct pathobiological properties. To faithfully study scrapie strain variability in natural sheep isolates, transgenic mice expressing sheep cellular prion protein (PrP) are used. In this study, we used two of such models to bioassay 20 scrapie isolates from the Spain-France-Andorra transboundary territory. Animals were intracerebrally inoculated and survival periods, proteinase K-resistant PrP (PrP) banding patterns, lesion profiles and PrP distribution were studied. Inocula showed a remarkable homogeneity on banding patterns, all of them but one showing 19-kDa PrP. However, a number of isolates caused accumulation of 21-kDa PrP in TgShp XI. A different subgroup of isolates caused long survival periods and presence of 21-kDa PrP in Tg338 mice. It seemed that one major 19-kDa prion isoform and two distinct 21-kDa variants coexisted in source inocula, and that they could be separated by bioassay in each transgenic model. The reason why each model favours a specific component of the mixture is unknown, although PrP expression level may play a role. Our results indicate that coinfection with more than one substrain is more frequent than infection with a single component.
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http://dx.doi.org/10.1038/s41598-020-61977-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081250PMC
March 2020

Correlation between Bioassay and Protein Misfolding Cyclic Amplification for Variant Creutzfeldt-Jakob Disease Decontamination Studies.

mSphere 2020 Jan 29;5(1). Epub 2020 Jan 29.

Pathogenesis and Control of Chronic Infections, Etablissement Français du Sang, INSERM, Université de Montpellier, Montpellier, France

To date, approximately 500 iatrogenic Creutzfeldt-Jakob disease cases have been reported worldwide, most of them resulting from cadaveric dura mater graft and from the administration of prion-contaminated human growth hormone. The unusual resistance of prions to decontamination processes, their large tissue distribution, and the uncertainty about the prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the general population lead to specific recommendations regarding identification of tissue at risk and reprocessing of reusable medical devices, including the use of dedicated treatment for prion inactivation. We previously described an assay, called Surf-PMCA, which allowed us to classify prion decontamination treatments according to their efficacy on vCJD prions by monitoring residual seeding activity (RSA). Here, we used a transgenic mouse line permissive to vCJD prions to study the correlation between the RSA measured and the infectivity. Implantation in mouse brains of prion-contaminated steel wires subjected to different decontamination procedures allows us to demonstrate a good concordance between RSA measured by Surf-PMCA () and residual infectivity (). These experiments emphasize the strength of the Surf-PMCA method as a rapid and sensitive assay for the evaluation of prion decontamination procedures and also confirm the lack of efficacy of several marketed reagents on vCJD prion decontamination. Creutzfeldt-Jakob diseases are neurodegenerative disorders for which transmission linked to medical procedures have been reported in hundreds of patients. As prion diseases, they are characterized by an unusual resistance to conventional decontamination processes. Moreover, their large tissue distribution and the ability of prions to attach to many surfaces raised the risk of transmission in health care facilities. It is therefore of major importance that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated for prion inactivation. We previously described an assay, which allowed us to classify accurately prion decontamination treatments according to their efficacy on variant Creutzfeldt-Jakob disease. The significance of this study is in demonstrating the concordance between previous results and infectivity studies in transgenic mice. Furthermore, commercial reagents currently used in hospitals were tested by both protocols, and we observed that most of them were ineffective on human prions.
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http://dx.doi.org/10.1128/mSphere.00649-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992370PMC
January 2020

Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway.

Commun Biol 2019 4;2:363. Epub 2019 Oct 4.

1VIM, INRA, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

The dynamics of aggregation and structural diversification of misfolded, host-encoded proteins in neurodegenerative diseases are poorly understood. In many of these disorders, including Alzheimer's, Parkinson's and prion diseases, the misfolded proteins are self-organized into conformationally distinct assemblies or strains. The existence of intrastrain structural heterogeneity is increasingly recognized. However, the underlying processes of emergence and coevolution of structurally distinct assemblies are not mechanistically understood. Here, we show that early prion replication generates two subsets of structurally different assemblies by two sequential processes of formation, regardless of the strain considered. The first process corresponds to a quaternary structural convergence, by reducing the parental strain polydispersity to generate small oligomers. The second process transforms these oligomers into larger ones, by a secondary autocatalytic templating pathway requiring the prion protein. This pathway provides mechanistic insights into prion structural diversification, a key determinant for prion adaptation and toxicity.
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http://dx.doi.org/10.1038/s42003-019-0608-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778151PMC
May 2020

Prion strain-dependent tropism is maintained between spleen and granuloma and relies on lymphofollicular structures.

Sci Rep 2019 10 10;9(1):14656. Epub 2019 Oct 10.

VIM, INRA, Université Paris-Saclay, 78350, Jouy-en-Josas, France.

In peripherally acquired prion diseases, prions move through several tissues of the infected host, notably in the lymphoid tissue, long before the occurrence of neuroinvasion. Accumulation can even be restricted to the lymphoid tissue without neuroinvasion and clinical disease. Several experimental observations indicated that the presence of differentiated follicular dendritic cells (FDCs) in the lymphoid structures and the strain type are critical determinants of prion extraneural replication. In this context, the report that granulomatous structures apparently devoid of FDCs could support prion replication raised the question of the requirements for prion lymphotropism. The report also raised the possibility that nonlymphoid tissue-tropic prions could actually target these inflammatory structures. To investigate these issues, we examined the capacity of closely related prions, albeit with opposite lymphotropism (or FDC dependency), for establishment in experimentally-induced granuloma in ovine PrP transgenic mice. We found a positive correlation between the prion capacity to accumulate in the lymphoid tissue and granuloma, regardless of the prion detection method used. Surprisingly, we also revealed that the accumulation of prions in granulomas involved lymphoid-like structures associated with the granulomas and containing cells that stain positive for PrP, Mfge-8 but not CD45 that strongly suggest FDCs. These results suggest that the FDC requirement for prion replication in lymphoid/inflammatory tissues may be strain-dependent.
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http://dx.doi.org/10.1038/s41598-019-51084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787085PMC
October 2019

Causative Links between Protein Aggregation and Oxidative Stress: A Review.

Int J Mol Sci 2019 Aug 9;20(16). Epub 2019 Aug 9.

Institut Curie, PSL Research University, CNRS UMR3348, Université Paris-Sud, Université Paris-Saclay, 91400 Orsay, France.

Compelling evidence supports a tight link between oxidative stress and protein aggregation processes, which are noticeably involved in the development of proteinopathies, such as Alzheimer's disease, Parkinson's disease, and prion disease. The literature is tremendously rich in studies that establish a functional link between both processes, revealing that oxidative stress can be either causative, or consecutive, to protein aggregation. Because oxidative stress monitoring is highly challenging and may often lead to artefactual results, cutting-edge technical tools have been developed recently in the redox field, improving the ability to measure oxidative perturbations in biological systems. This review aims at providing an update of the previously known functional links between oxidative stress and protein aggregation, thereby revisiting the long-established relationship between both processes.
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http://dx.doi.org/10.3390/ijms20163896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719959PMC
August 2019

Thermostability as a highly dependent prion strain feature.

Sci Rep 2019 08 6;9(1):11396. Epub 2019 Aug 6.

Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos, Madrid, Spain.

Prion diseases are caused by the conversion of physiological PrP into the pathogenic misfolded protein PrP, conferring new properties to PrP that vary upon prion strains. In this work, we analyze the thermostability of three prion strains (BSE, RML and 22L) that were heated at 98 °C for 2 hours. PrP resistance to proteinase K (PrP), residual infectivity by mouse bioassay and in vitro templating activity by protein misfolding cyclic amplification (PMCA) were studied. Heated strains showed a huge loss of PrP and a radically different infectivity loss: RML was the most thermolabile strain (6 to 7 log10 infectivity loss), followed by 22L (5 log10) while BSE was the most thermostable strain with low or null infectivity reduction showing a clear dissociation between PrP and infectivity. These results indicate that thermostability is a strain-specific feature, measurable by PMCA and mouse bioassay, and a great tool to distinguish prion strains.
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http://dx.doi.org/10.1038/s41598-019-47781-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684573PMC
August 2019

Heterogeneity and Architecture of Pathological Prion Protein Assemblies: Time to Revisit the Molecular Basis of the Prion Replication Process?

Viruses 2019 05 10;11(5). Epub 2019 May 10.

Molecular Virology and Immunology Unit (VIM), INRA, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

Prions are proteinaceous infectious agents responsible for a range of neurodegenerative diseases in animals and humans. Prion particles are assemblies formed from a misfolded, β-sheet rich, aggregation-prone isoform (PrP) of the host-encoded cellular prion protein (PrP). Prions replicate by recruiting and converting PrP into PrP, by an autocatalytic process. PrP is a pleiomorphic protein as different conformations can dictate different disease phenotypes in the same host species. This is the basis of the strain phenomenon in prion diseases. Recent experimental evidence suggests further structural heterogeneity in PrP assemblies within specific prion populations and strains. Still, this diversity is rather seen as a size continuum of assemblies with the same core structure, while analysis of the available experimental data points to the existence of structurally distinct arrangements. The atomic structure of PrP has not been elucidated so far, making the prion replication process difficult to understand. All currently available models suggest that PrP assemblies exhibit a PrP subunit as core constituent, which was recently identified. This review summarizes our current knowledge on prion assembly heterogeneity down to the subunit level and will discuss its importance with regard to the current molecular principles of the prion replication process.
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http://dx.doi.org/10.3390/v11050429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563208PMC
May 2019

High-Pressure Response of Amyloid Folds.

Viruses 2019 02 28;11(3). Epub 2019 Feb 28.

Institut National de la Recherche Agronomique, UR892, Virologie Immunologie Moléculaires, F-78350 Jouy-en-Josas, France.

The abnormal protein aggregates in progressive neurodegenerative disorders, such as Alzheimer's, Parkinson's and prion diseases, adopt a generic structural form called amyloid fibrils. The precise amyloid fold can differ between patients and these differences are related to distinct neuropathological phenotypes of the diseases. A key focus in current research is the molecular mechanism governing such structural diversity, known as amyloid polymorphism. In this review, we focus on our recent work on recombinant prion protein (recPrP) and the use of pressure as a variable for perturbing protein structure. We suggest that the amyloid polymorphism is based on volumetric features. Accordingly, pressure is the thermodynamic parameter that fits best to exploit volume differences within the states of a chemical reaction, since it shifts the equilibrium constant to the state that has the smaller volume. In this context, there are analogies with the process of correct protein folding, the high pressure-induced effects of which have been studied for more than a century and which provides a valuable source of inspiration. We present a short overview of this background and review our recent results regarding the folding, misfolding, and aggregation-disaggregation of recPrP under pressure. We present preliminary experiments aimed at identifying how prion protein fibril diversity is related to the quaternary structure by using pressure and varying protein sequences. Finally, we consider outstanding questions and testable mechanistic hypotheses regarding the multiplicity of states in the amyloid fold.
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http://dx.doi.org/10.3390/v11030202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466028PMC
February 2019

Pressure Reveals Unique Conformational Features in Prion Protein Fibril Diversity.

Sci Rep 2019 02 26;9(1):2802. Epub 2019 Feb 26.

Institut National de la Recherche Agronomique, UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.

The prion protein (PrP) misfolds and assembles into a wide spectrum of self-propagating quaternary structures, designated PrP. These various PrP superstructures can be functionally different, conferring clinically distinctive symptomatology, neuropathology and infectious character to the associated prion diseases. However, a satisfying molecular basis of PrP structural diversity is lacking in the literature. To provide mechanistic insights into the etiology of PrP polymorphism, we have engineered a set of 6 variants of the human protein and obtained PrP amyloid fibrils. We show that pressure induces dissociation of the fibrils, albeit with different kinetics. In addition, by focusing on the generic properties of amyloid fibrils, such as the thioflavin T binding capacities and the PK-resistance, we reveal an unprecedented structure-barostability phenomenological relationship. We propose that the structural diversity of PrP fibrils encompass a multiplicity of packing defects (water-excluded cavities) in their hydrophobic cores, and that the resultant sensitivity to pressure should be considered as a general molecular criterion to accurately define fibril morphotypes. We anticipate that our insights into sequence-dependent fibrillation and conformational stability will shed light on the highly-nuanced prion strain phenomenon and open the opportunity to explain different PrP conformations in terms of volumetric physics.
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http://dx.doi.org/10.1038/s41598-019-39261-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391531PMC
February 2019

Epigenetic Control of the Notch and Eph Signaling Pathways by the Prion Protein: Implications for Prion Diseases.

Mol Neurobiol 2019 Mar 11;56(3):2159-2173. Epub 2018 Jul 11.

INSERM UMR 1124, 75006, Paris, France.

Among the ever-growing number of self-replicating proteins involved in neurodegenerative diseases, the prion protein PrP remains the most infamous for its central role in transmissible spongiform encephalopathies (TSEs). In these diseases, pathogenic prions propagate through a seeding mechanism, where normal PrP molecules are converted into abnormally folded scrapie isoforms termed PrP. Since its discovery over 30 years ago, much advance has contributed to define the host-encoded cellular prion protein PrP as a critical relay of prion-induced neuronal cell demise. A current consensual view is that the conversion of PrP into PrP in neuronal cells diverts the former from its normal function with subsequent molecular alterations affecting synaptic plasticity. Here, we report that prion infection is associated with reduced expression of key effectors of the Notch pathway in vitro and in vivo, recapitulating changes fostered by the absence of PrP. We further show that both prion infection and PrP depletion promote drastic alterations in the expression of a defined set of Eph receptors and their ephrin ligands, which represent important players in synaptic function. Our data indicate that defects in the Notch and Eph axes can be mitigated in response to histone deacetylase inhibition in PrP-depleted as well as prion-infected cells. We thus conclude that infectious prions cause a loss-of-function phenotype with respect to Notch and Eph signaling and that these alterations are sustained by epigenetic mechanisms.
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http://dx.doi.org/10.1007/s12035-018-1193-7DOI Listing
March 2019

Prion Strains and Transmission Barrier Phenomena.

Pathogens 2018 Jan 1;7(1). Epub 2018 Jan 1.

Virologie et Immunologie Moléculaires, INRA, Université Paris-Saclay, UR892, 78350 Jouy-en-Josas, France.

Several experimental evidences show that prions are non-conventional pathogens, which physical support consists only in proteins. This finding raised questions regarding the observed prion strain-to-strain variations and the species barrier that happened to be crossed with dramatic consequences on human health and veterinary policies during the last 3 decades. This review presents a focus on a few advances in the field of prion structure and prion strains characterization: from the historical approaches that allowed the concept of prion strains to emerge, to the last results demonstrating that a prion strain may in fact be a combination of a few quasi species with subtle biophysical specificities. Then, we will focus on the current knowledge on the factors that impact species barrier strength and species barrier crossing. Finally, we present probable scenarios on how the interaction of strain properties with host characteristics may account for differential selection of new conformer variants and eventually species barrier crossing.
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http://dx.doi.org/10.3390/pathogens7010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874731PMC
January 2018

Reversible unfolding of infectious prion assemblies reveals the existence of an oligomeric elementary brick.

PLoS Pathog 2017 Sep 7;13(9):e1006557. Epub 2017 Sep 7.

INRA, Université Paris-Saclay, UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France.

Mammalian prions, the pathogens that cause transmissible spongiform encephalopathies, propagate by self-perpetuating the structural information stored in the abnormally folded, aggregated conformer (PrPSc) of the host-encoded prion protein (PrPC). To date, no structural model related to prion assembly organization satisfactorily describes how strain-specified structural information is encoded and by which mechanism this information is transferred to PrPC. To achieve progress on this issue, we correlated the PrPSc quaternary structural transition from three distinct prion strains during unfolding and refolding with their templating activity. We reveal the existence of a mesoscopic organization in PrPSc through the packing of a highly stable oligomeric elementary subunit (suPrP), in which the strain structural determinant (SSD) is encoded. Once kinetically trapped, this elementary subunit reversibly loses all replicative information. We demonstrate that acquisition of the templating interface and infectivity requires structural rearrangement of suPrP, in concert with its condensation. The existence of such an elementary brick scales down the SSD support to a small oligomer and provide a basis of reflexion for prion templating process and propagation.
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http://dx.doi.org/10.1371/journal.ppat.1006557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589264PMC
September 2017

Region-specific protein misfolding cyclic amplification reproduces brain tropism of prion strains.

J Biol Chem 2017 10 15;292(40):16688-16696. Epub 2017 Aug 15.

From the INSERM, UMR S1127, 75013 Paris, France,

Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrP). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrP deposits within the brain and the spongiform lesions they induce. The mechanisms involved in this strain-specific targeting of distinct brain regions still are a fundamental, unresolved question in prion research. To address this question, we exploited a prion conversion assay, protein misfolding cyclic amplification (PMCA), by using experimental scrapie and human prion strains as seeds and specific brain regions from mice and humans as substrates. We show here that region-specific PMCA in part reproduces the specific brain targeting observed in experimental, acquired, and sporadic Creutzfeldt-Jakob diseases. Furthermore, we provide evidence that, in addition to cellular prion protein, other region- and species-specific molecular factors influence the strain-dependent prion conversion process. This important step toward understanding prion strain propagation in the human brain may impact research on the molecular factors involved in protein misfolding and the development of ultrasensitive methods for diagnosing prion disease.
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http://dx.doi.org/10.1074/jbc.M117.793646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633130PMC
October 2017

Distribution and Quantitative Estimates of Variant Creutzfeldt-Jakob Disease Prions in Tissues of Clinical and Asymptomatic Patients.

Emerg Infect Dis 2017 06;23(6):946-956

In the United-Kingdom, ≈1 of 2,000 persons could be infected with variant Creutzfeldt-Jakob disease (vCJD). Therefore, risk of transmission of vCJD by medical procedures remains a major concern for public health authorities. In this study, we used in vitro amplification of prions by protein misfolding cyclic amplification (PMCA) to estimate distribution and level of the vCJD agent in 21 tissues from 4 patients who died of clinical vCJD and from 1 asymptomatic person with vCJD. PMCA identified major levels of vCJD prions in a range of tissues, including liver, salivary gland, kidney, lung, and bone marrow. Bioassays confirmed that the quantitative estimate of levels of vCJD prion accumulation provided by PMCA are indicative of vCJD infectivity levels in tissues. Findings provide critical data for the design of measures to minimize risk for iatrogenic transmission of vCJD.
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http://dx.doi.org/10.3201/eid2306.161734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443438PMC
June 2017

The double life of the ribosome: When its protein folding activity supports prion propagation.

Prion 2017 Mar;11(2):89-97

f Université de Rennes 1, CNRS UMR 6290 IGDR , Rennes , France.

It is no longer necessary to demonstrate that ribosome is the central machinery of protein synthesis. But it is less known that it is also key player of the protein folding process through another conserved function: the protein folding activity of the ribosome (PFAR). This ribozyme activity, discovered more than 2 decades ago, depends upon the domain V of the large rRNA within the large subunit of the ribosome. Surprisingly, we discovered that anti-prion compounds are also potent PFAR inhibitors, highlighting an unexpected link between PFAR and prion propagation. In this review, we discuss the ancestral origin of PFAR in the light of the ancient RNA world hypothesis. We also consider how this ribosomal activity fits into the landscape of cellular protein chaperones involved in the appearance and propagation of prions and other amyloids in mammals. Finally, we examine how drugs targeting the protein folding activity of the ribosome could be active against mammalian prion and other protein aggregation-based diseases, making PFAR a promising therapeutic target for various human protein misfolding diseases.
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http://dx.doi.org/10.1080/19336896.2017.1303587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399909PMC
March 2017

A stretch of residues within the protease-resistant core is not necessary for prion structure and infectivity.

Prion 2017 01 8;11(1):25-30. Epub 2017 Feb 8.

a VIM, INRA, Université Paris-Saclay , Jouy-en-Josas , France.

Mapping out regions of PrP influencing prion conversion remains a challenging issue complicated by the lack of prion structure. The portion of PrP associated with infectivity contains the α-helical domain of the correctly folded protein and turns into a β-sheet-rich insoluble core in prions. Deletions performed so far inside this segment essentially prevented the conversion. Recently we found that deletion of the last C-terminal residues of the helix H2 was fully compatible with prion conversion in the RK13-ovPrP cell culture model, using 3 different infecting strains. This was in agreement with preservation of the overall PrP structure even after removal of up to one-third of this helix. Prions with internal deletion were infectious for cells and mice expressing the wild-type PrP and they retained prion strain-specific characteristics. We thus identified a piece of the prion domain that is neither necessary for the conformational transition of PrP nor for the formation of a stable prion structure.
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http://dx.doi.org/10.1080/19336896.2016.1274851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360129PMC
January 2017

Cerebellar compartmentation of prion pathogenesis.

Brain Pathol 2018 03 10;28(2):240-263. Epub 2017 Apr 10.

Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires & Intégratives, CNRS UPR 3212, Strasbourg, France.

In prion diseases, the brain lesion profile is influenced by the prion "strain" properties, the invasion route to the brain, and still unknown host cell-specific parameters. To gain insight into those endogenous factors, we analyzed the histopathological alterations induced by distinct prion strains in the mouse cerebellum. We show that 22L and ME7 scrapie prion proteins (PrP , PrP ), but not bovine spongiform encephalopathy PrP , accumulate in a reproducible parasagittal banding pattern in the cerebellar cortex of infected mice. Such banding pattern of PrP aggregation did not depend on the neuroinvasion route, but coincided with the parasagittal compartmentation of the cerebellum mostly defined by the expression of zebrins, such as aldolase C and the excitatory amino acid transporter 4, in Purkinje cells. We provide evidence that Purkinje cells display a differential, subtype-specific vulnerability to 22L prions with zebrin-expressing Purkinje cells being more resistant to prion toxicity, while in stripes where PrP accumulated most zebrin-deficient Purkinje cells are lost and spongiosis accentuated. In addition, in PrP stripes, enhanced reactive astrocyte processes associated with microglia activation support interdependent events between the topographic pattern of Purkinje cell death, reactive gliosis and PrP accumulation. Finally, we find that in preclinically-ill mice prion infection promotes at the membrane of astrocytes enveloping Purkinje cell excitatory synapses, upregulation of tumor necrosis factor-α receptor type 1 (TNFR1), a key mediator of the neuroinflammation process. These overall data show that Purkinje cell sensitivity to prion insult is locally restricted by the parasagittal compartmentation of the cerebellum, and that perisynaptic astrocytes may contribute to prion pathogenesis through prion-induced TNFR1 upregulation.
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http://dx.doi.org/10.1111/bpa.12503DOI Listing
March 2018

Divergent prion strain evolution driven by PrP expression level in transgenic mice.

Nat Commun 2017 01 23;8:14170. Epub 2017 Jan 23.

Virologie Immunologie Moléculaires (VIM), INRA, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrP into PrP. Structurally distinct PrP conformers can give rise to multiple prion strains. Constrained interactions between PrP and different PrP strains can in turn lead to certain PrP (sub)populations being selected for cross-species transmission, or even produce mutation-like events. By contrast, prion strains are generally conserved when transmitted within the same species, or to transgenic mice expressing homologous PrP. Here, we compare the strain properties of a representative sheep scrapie isolate transmitted to a panel of transgenic mouse lines expressing varying levels of homologous PrP. While breeding true in mice expressing PrP at near physiological levels, scrapie prions evolve consistently towards different strain components in mice beyond a certain threshold of PrP overexpression. Our results support the view that PrP gene dosage can influence prion evolution on homotypic transmission.
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http://dx.doi.org/10.1038/ncomms14170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264111PMC
January 2017

Detection of prions in the plasma of presymptomatic and symptomatic patients with variant Creutzfeldt-Jakob disease.

Sci Transl Med 2016 12;8(370):370ra182

Etablissement Français du Sang, INSERM, Université de Montpellier, UMR 1058, TransDiag, F-34184 Montpellier, France.

Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease resulting from the consumption of meat products contaminated by the agent causing bovine spongiform encephalopathy. Evidence supporting the presence of a population of silent carriers that can potentially transmit the disease through blood transfusion is increasing. The development of a blood-screening assay for both symptomatic vCJD patients and asymptomatic carriers is urgently required. We show that a diagnostic assay combining plasminogen-bead capture and protein misfolding cyclic amplification (PMCA) technologies consistently detected minute amounts of abnormal prion protein from French and British vCJD cases in the required femtomolar range. This assay allowed the blinded identification of 18 patients with clinical vCJD among 256 plasma samples from the two most affected countries, with 100% sensitivity [95% confidence interval (CI), 81.5 to 100%], 99.2% analytical specificity (95% CI, 95.9 to 100%), and 100% diagnostic specificity (95% CI, 96.5 to 100%). This assay also allowed the detection of silent carriage of prions 1.3 and 2.6 years before the clinical onset in two blood donors who later developed vCJD. These data provide a key step toward the validation of this PMCA technology as a blood-based diagnostic test for vCJD and support its potential for detecting presymptomatic patients, a prerequisite for limiting the risk of vCJD transmission through blood transfusion.
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http://dx.doi.org/10.1126/scitranslmed.aag1257DOI Listing
December 2016

Prion Diseases in Animals and Zoonotic Potential.

Food Saf (Tokyo) 2016 Dec 7;4(4):105-109. Epub 2016 Dec 7.

Centro de Investigacion en Sanidad Animal (CISA-INIA), Valdeolmos, Madrid, Spain.

Dietary exposure to Bovine Spongiform Encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt-Jakob disease (vCJD) in humans. To date, BSE agent is the only recognized zoonotic prion. Despite the variety of transmissible spongiform encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants, there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt-Jakob disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modelling of the "species barrier," the biological phenomenon that limits TSE agents' propagation from one species to another. In the past decade, mice genetically engineered to express normal forms of the human prion protein have proven to be essential in studying human prions pathogenesis and modelling the capacity of TSEs to cross the human species barrier. To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrP (HuPrP-Tg). Two lines of mice expressing different forms of the human PrP (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents. These transmission experiments confirm the ability of BSE prions to propagate in 129M-HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goats to a greater degree than the BSE agent in cattle, and that these agents can convey molecular properties and be neuropathologically indistinguishable from vCJD. However, homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species, suggesting a higher transmission barrier for 129V-PrP variant. Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice. Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
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http://dx.doi.org/10.14252/foodsafetyfscj.2016021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989209PMC
December 2016