Publications by authors named "Juan Carlos Espinosa"

49 Publications

TREM2 expression in the brain and biological fluids in prion diseases.

Acta Neuropathol 2021 Apr 21. Epub 2021 Apr 21.

Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), L'Hospitalet de Llobregat, Spain.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78-0.90) and neurological controls (AUC = 0.73-0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer's disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring.
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http://dx.doi.org/10.1007/s00401-021-02296-1DOI Listing
April 2021

Classical scrapie in small ruminants is caused by at least four different prion strains.

Vet Res 2021 Apr 15;52(1):57. Epub 2021 Apr 15.

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

The diversity of goat scrapie strains in Europe has recently been studied using bioassays in a wide collection of rodent models, resulting in the classification of classical scrapie into four different categories. However, the sole use of the first passage does not lead to isolate adaptation and identification of the strains involved and might therefore lead to misclassification of some scrapie isolates. Therefore, this work reports the complete transmission study of a wide collection of goat transmissible spongiform encephalopathy (TSE) isolates by intracranial inoculation in two transgenic mouse lines overexpressing either small ruminant (TgGoat-ARQ) or bovine (TgBov) PrP. To compare scrapie strains in sheep and goats, sheep scrapie isolates from different European countries were also included in the study. Once the species barrier phenomenon was overcome, an accurate classification of the isolates was attained. Thus, the use of just two rodent models allowed us to fully differentiate at least four different classical scrapie strains in small ruminants and to identify isolates containing mixtures of strains. This work reinforces the idea that classical scrapie in small ruminants is a prion disease caused by multiple different prion strains and not by a single strain, as is the case for epidemic classical bovine spongiform encephalopathy (BSE-C). In addition, the clear dissimilarity between the different scrapie strains and BSE-C does not support the idea that classical scrapie is the origin of epidemic BSE-C.
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http://dx.doi.org/10.1186/s13567-021-00929-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048364PMC
April 2021

PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice.

Elife 2021 04 14;10. Epub 2021 Apr 14.

Fondazione IRCCS Istituto Neurologico Carlo Besta, Division of Neurology 5 and Neuropathology, Milan, Italy.

Background: Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA).

Methods: In this work, we have challenged PMCA-generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology.

Results: All inoculated mice developed mild spongiform changes, astroglial activation, and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate.

Conclusions: Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious.

Funding: This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer's Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (SPEEDY) to FM; by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) to JMT and JCE; AM-M was supported by a fellowship from the INIA (FPI-SGIT-2015-02).
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http://dx.doi.org/10.7554/eLife.65311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064759PMC
April 2021

Two distinct conformers of PrP type 1 of sporadic Creutzfeldt-Jakob disease with codon 129VV genotype faithfully propagate in vivo.

Acta Neuropathol Commun 2021 03 25;9(1):55. Epub 2021 Mar 25.

Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.

Current classifications of sporadic Creutzfeldt-Jakob disease (sCJD) identify five subtypes associated with different disease phenotypes. Most of these histopathological phenotypes (histotypes) co-distribute with distinct pairings of methionine (M)/valine (V) genotypes at codon 129 of the prion protein (PrP) gene and the type (1 or 2) of the disease-associated PrP (PrP). Types 1 and 2 are defined by the molecular mass (~ 21 kDa and ~ 19 kDa, respectively) of the unglycosylated isoform of the proteinase K-resistant PrP (resPrP). We recently reported that the sCJDVV1 subtype (129VV homozygosity paired with PrP type 1, T1) shows an electrophoretic profile where the resPrP unglycosylated isoform is characterized by either one of two single bands of ~ 20 kDa (T1) and ~ 21 kDa (T1), or a doublet of ~ 21-20 kDa (T1). We also showed that T1 and T1 in sCJDVV have different conformational features but are associated with indistinguishable histotypes. The presence of three distinct molecular profiles of T1 is unique and raises the issue as to whether T1 and T1 represent distinct prion strains. To answer this question, brain homogenates from sCJDVV cases harboring each of the three resPrP profiles, were inoculated to transgenic (Tg) mice expressing the human PrP-129M or PrP-129V genotypes. We found that T1 and T1 were faithfully replicated in Tg129V mice. Electrophoretic profile and incubation period of mice challenged with T1 resembled those of mice inoculated with T1 and T1, respectively. As in sCJDVV1, Tg129V mice challenged with T1 and T1 generated virtually undistinguishable histotypes. In Tg129M mice, T1 was not replicated while T1 and T1 generated a ~ 21-20  kDa doublet after lengthier incubation periods. On second passage, Tg129M mice incubation periods and regional PrP accumulation significantly differed in T1 and T1 challenged mice. Combined, these data indicate that T1 and T1 resPrP represent distinct human prion strains associated with partially overlapping histotypes.
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http://dx.doi.org/10.1186/s40478-021-01132-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995586PMC
March 2021

Allelic Interference in Prion Replication Is Modulated by the Convertibility of the Interfering PrP and Other Host-Specific Factors.

mBio 2021 03 16;12(2). Epub 2021 Mar 16.

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

Early studies in transgenic mouse lines have shown that the coexpression of endogenous murine prion protein (PrP) and transgenic PrP from another species either inhibits or allows the propagation of prions, depending on the infecting prion strain and interacting protein species. The way whereby this phenomenon, so-called "interference," is modulated remains to be determined. In this study, different transgenic mouse lines were crossbred to produce mice coexpressing bovine and porcine PrP, bovine and murine PrP, or murine and porcine PrP These animals and their respective hemizygous controls were inoculated with several prion strains from different sources (cattle, mice, and pigs) to examine the effects of the simultaneous presence of PrP from two different species. Our results indicate interference with the infection process, manifested as extended survival times and reduced attack rates. The interference with the infectious process was reduced or absent when the potentiality interfering PrP species was efficiently converted by the inoculated agent. However, the propagation of the endogenous murine PrP was favored, allowing us to speculate that host-specific factors may disturb the interference caused by the coexpression of an exogenous second PrP Prion propagation can be interfered with by the expression of a second prion protein in the host. In the present study, we investigated prion propagation in a host expressing two different prion protein genes. Our findings indicate that the ability of the second prion protein to interfere with prion propagation is related to the transmissibility of the prion in the host expressing only the interfering prion protein. The interference detected occurs in a prion strain-dependent manner. Interestingly, a bias favoring the propagation of the murine PrP allele has been observed. These results open the door to future studies in order to determine the role of host factors other than the PrP amino acid sequence in the interference in prion propagation.
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http://dx.doi.org/10.1128/mBio.03508-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092304PMC
March 2021

Met -Glu residues in human PrP β2-α2 loop account for evolutionary resistance to prion infection.

Neuropathol Appl Neurobiol 2021 Jun 22;47(4):506-518. Epub 2020 Dec 22.

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

Aims: The amino acid sequence of prion protein (PrP) is a key determinant in the transmissibility of prion diseases. While PrP sequence is highly conserved among mammalian species, minor changes in the PrP amino acid sequence may confer alterations in the transmissibility of prion diseases. Classical bovine spongiform encephalopathy (C-BSE) is the only zoonotic prion strain reported to date causing variant Creutzfeldt-Jacob disease (vCJD) in humans, although experimental transmission points to atypical L-BSE and some classical scrapie isolates as also zoonotic. The precise molecular elements in the human PrP sequence that limit the transmissibility of prion strains such as sheep/goat scrapie or cervid chronic wasting disease (CWD) are not well known.

Methods: The transmissibility of a panel of diverse prions from different species was compared in transgenic mice expressing either wild-type human PrP (MDE-HuTg340) or a mutated human PrP harbouring Val -Gln amino acid changes (VDQ-HuTg372) in the β2-α2 loop instead of Met -Glu wild-type variants.

Results: VDQ-HuTg372 mice were more susceptible to prions than MDE-HuTg340 mice in a strain-dependent manner.

Conclusions: Met -Glu amino acid residues present in wild-type human PrP are molecular determinants that limit the propagation of most prion strains assayed in the human PrP context.
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http://dx.doi.org/10.1111/nan.12676DOI Listing
June 2021

Transgenic mouse models for the study of prion diseases.

Prog Mol Biol Transl Sci 2020 11;175:147-177. Epub 2020 Sep 11.

Centro de Investigación en Sanidad Animal (CISA-INIA), Madrid, Spain. Electronic address:

Prions are unique agents that challenge the molecular biology dogma by transmitting information on the protein level. They cause neurodegenerative diseases that lack of any cure or treatment called transmissible spongiform encephalopathies. The function of the normal form of the prion protein, the exact mechanism of prion propagation between species as well as at the cellular level and neuron degeneration remains elusive. However, great amount of information known for all these aspects has been achieved thanks to the use of animal models and more precisely to transgenic mouse models. In this chapter, the main contributions of these powerful research tools in the prion field are revised.
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http://dx.doi.org/10.1016/bs.pmbts.2020.08.007DOI Listing
September 2020

MicroRNA Alterations in a Tg501 Mouse Model of Prion Disease.

Biomolecules 2020 06 15;10(6). Epub 2020 Jun 15.

Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, University of Zaragoza, 50013 Zaragoza, Spain.

MicroRNAs (miRNAs) may contribute to the development and pathology of many neurodegenerative diseases, including prion diseases. They are also promising biomarker candidates due to their stability in body fluids. We investigated miRNA alterations in a Tg501 mouse model of prion diseases that expresses a transgene encoding the goat prion protein (). Tg501 mice intracranially inoculated with mouse-adapted goat scrapie were compared with age-matched, mock inoculated controls in preclinical and clinical stages. Small RNA sequencing from the cervical spinal cord indicated that miR-223-3p, miR-151-3p, and miR-144-5p were dysregulated in scrapie-inoculated animals before the onset of symptoms. In clinical-stage animals, 23 significant miRNA alterations were found. These miRNAs were predicted to modify the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including prion disease, extracellular matrix interactions, glutaminergic synapse, axon guidance, and transforming growth factor-beta signaling. MicroRNAs miR-146a-5p (up in cervical spinal cord) and miR-342-3p (down in cervical spinal cord, cerebellum and plasma), both indicated in neurodegenerative diseases earlier, were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Minimal changes observed before the disease onset suggests that most miRNA alterations observed here are driven by advanced prion-associated pathology, possibly limiting their use as diagnostic markers. However, the results encourage further mechanistic studies on miRNA-regulated pathways involved in these neurodegenerative conditions.
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http://dx.doi.org/10.3390/biom10060908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355645PMC
June 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

Radical Change in Zoonotic Abilities of Atypical BSE Prion Strains as Evidenced by Crossing of Sheep Species Barrier in Transgenic Mice.

Emerg Infect Dis 2020 06;26(6):1130-1139

Classical bovine spongiform encephalopathy (BSE) is the only zoonotic prion disease described to date. Although the zoonotic potential of atypical BSE prions have been partially studied, an extensive analysis is still needed. We conducted a systematic study by inoculating atypical BSE isolates from different countries in Europe into transgenic mice overexpressing human prion protein (PrP): TgMet, TgMet/Val, and TgVal. L-type BSE showed a higher zoonotic potential in TgMet mice than classical BSE, whereas Val-PrP variant was a strong molecular protector against L-type BSE prions, even in heterozygosis. H-type BSE could not be transmitted to any of the mice. We also adapted 1 H- and 1 L-type BSE isolate to sheep-PrP transgenic mice and inoculated them into human-PrP transgenic mice. Atypical BSE prions showed a modification in their zoonotic ability after adaptation to sheep-PrP producing agents able to infect TgMet and TgVal, bearing features that make them indistinguishable of sporadic Creutzfeldt-Jakob disease prions.
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http://dx.doi.org/10.3201/eid2606.181790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258450PMC
June 2020

Porcine Prion Protein as a Paradigm of Limited Susceptibility to Prion Strain Propagation.

J Infect Dis 2021 Mar;223(6):1103-1112

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

Although experimental transmission of bovine spongiform encephalopathy (BSE) to pigs and transgenic mice expressing pig cellular prion protein (PrPC) (porcine PrP [PoPrP]-Tg001) has been described, no natural cases of prion diseases in pig were reported. This study analyzed pig-PrPC susceptibility to different prion strains using PoPrP-Tg001 mice either as animal bioassay or as substrate for protein misfolding cyclic amplification (PMCA). A panel of isolates representatives of different prion strains was selected, including classic and atypical/Nor98 scrapie, atypical-BSE, rodent scrapie, human Creutzfeldt-Jakob-disease and classic BSE from different species. Bioassay proved that PoPrP-Tg001-mice were susceptible only to the classic BSE agent, and PMCA results indicate that only classic BSE can convert pig-PrPC into scrapie-type PrP (PrPSc), independently of the species origin. Therefore, conformational flexibility constraints associated with pig-PrP would limit the number of permissible PrPSc conformations compatible with pig-PrPC, thus suggesting that pig-PrPC may constitute a paradigm of low conformational flexibility that could confer high resistance to the diversity of prion strains.
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http://dx.doi.org/10.1093/infdis/jiz646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006416PMC
March 2021

Characterization of goat prions demonstrates geographical variation of scrapie strains in Europe and reveals the composite nature of prion strains.

Sci Rep 2020 01 8;10(1):19. Epub 2020 Jan 8.

Wageningen BioVeterinary Research, Lelystad, the Netherlands.

Bovine Spongiform Encephalopathy (BSE) is the only animal prion which has been recognized as a zoonotic agent so far. The identification of BSE in two goats raised the need to reliably identify BSE in small ruminants. However, our understanding of scrapie strain diversity in small ruminants remains ill-defined, thus limiting the accuracy of BSE surveillance and spreading fear that BSE might lurk unrecognized in goats. We investigated prion strain diversity in a large panel of European goats by a novel experimental approach that, instead of assessing the neuropathological profile after serial transmissions in a single animal model, was based on the direct interaction of prion isolates with several recipient rodent models expressing small ruminants or heterologous prion proteins. The findings show that the biological properties of scrapie isolates display different patterns of geographical distribution in Europe and suggest that goat BSE could be reliably discriminated from a wide range of biologically and geographically diverse goat prion isolates. Finally, most field prion isolates showed composite strain features, with discrete strain components or sub-strains being present in different proportions in individual goats or tissues. This has important implications for understanding the nature and evolution of scrapie strains and their transmissibility to other species, including humans.
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http://dx.doi.org/10.1038/s41598-019-57005-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949283PMC
January 2020

The emergence of classical BSE from atypical/Nor98 scrapie.

Proc Natl Acad Sci U S A 2019 Dec 16. Epub 2019 Dec 16.

UMR Institut National de la Recherche Agronomique (INRA)/École Nationale Vétérinaire de Toulouse (ENVT) 1225, Interactions Hôtes Agents Pathogènes, 31076 Toulouse, France;

Atypical/Nor98 scrapie (AS) is a prion disease of small ruminants. Currently there are no efficient measures to control this form of prion disease, and, importantly, the zoonotic potential and the risk that AS might represent for other farmed animal species remains largely unknown. In this study, we investigated the capacity of AS to propagate in bovine PrP transgenic mice. Unexpectedly, the transmission of AS isolates originating from 5 different European countries to bovine PrP mice resulted in the propagation of the classical BSE (c-BSE) agent. Detection of prion seeding activity in vitro by protein misfolding cyclic amplification (PMCA) demonstrated that low levels of the c-BSE agent were present in the original AS isolates. C-BSE prion seeding activity was also detected in brain tissue of ovine PrP mice inoculated with limiting dilutions (endpoint titration) of ovine AS isolates. These results are consistent with the emergence and replication of c-BSE prions during the in vivo propagation of AS isolates in the natural host. These data also indicate that c-BSE prions, a known zonotic agent in humans, can emerge as a dominant prion strain during passage of AS between different species. These findings provide an unprecedented insight into the evolution of mammalian prion strain properties triggered by intra- and interspecies passage. From a public health perspective, the presence of c-BSE in AS isolates suggest that cattle exposure to small ruminant tissues and products could lead to new occurrences of c-BSE.
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http://dx.doi.org/10.1073/pnas.1915737116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936354PMC
December 2019

Transgenic mouse models expressing human and macaque prion protein exhibit similar prion susceptibility on a strain-dependent manner.

Sci Rep 2019 10 30;9(1):15699. Epub 2019 Oct 30.

Centro de Investigación en Sanidad Animal (INIA-CISA), 28130, Valdeolmos, Madrid, Spain.

Cynomolgus macaque has been used for the evaluation of the zoonotic potential of prion diseases, especially for classical-Bovine Spongiform Encephalopathy (classical-BSE) infectious agent. PrP amino acid sequence is considered to play a key role in the susceptibility to prion strains and only one amino acid change may alter this susceptibility. Macaque and human-PrP sequences have only nine amino acid differences, but the effect of these amino acid changes in the susceptibility to dissimilar prion strains is unknown. In this work, the transmissibility of a panel of different prions from several species was compared in transgenic mice expressing either macaque-PrP (TgMac) or human-PrP (Hu-Tg340). Similarities in the transmissibility of most prion strains were observed suggesting that macaque is an adequate model for the evaluation of human susceptibility to most of the prion strains tested. Interestingly, TgMac were more susceptible to classical-BSE strain infection than Hu-Tg340. This differential susceptibility to classical-BSE transmission should be taken into account for the interpretation of the results obtained in macaques. It could notably explain why the macaque model turned out to be so efficient (worst case model) until now to model human situation towards classical-BSE despite the limited number of animals inoculated in the laboratory experiments.
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http://dx.doi.org/10.1038/s41598-019-52155-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821920PMC
October 2019

RNA editing alterations define manifestation of prion diseases.

Proc Natl Acad Sci U S A 2019 09 6;116(39):19727-19735. Epub 2019 Sep 6.

Neurodegenerative Diseases Research Group, Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece;

Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt-Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.
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http://dx.doi.org/10.1073/pnas.1803521116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765247PMC
September 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

Nonpathogenic Heterologous Prions Can Interfere with Prion Infection in a Strain-Dependent Manner.

J Virol 2018 12 27;92(24). Epub 2018 Nov 27.

Centro de Investigación en Sanidad Animal, CISA-INIA, Madrid, Spain

Co-occurrence of different prion strains into the same host has been recognized as a natural phenomenon for several sporadic Creutzfeldt-Jakob disease (sCJD) patients and natural scrapie cases. The final outcome of prion coinfection is not easily predictable. In addition to the usual factors that influence prion conversion, the replication of one strain may entail positive or negative consequences to the other. The main aim of this study was to gain insights into the prion coinfection and interference concepts and their potential therapeutic implications. Here, different mouse models were challenged with several combinations of prion strains coupled on the basis of the lengths of their incubation periods and the existence/absence of a species barrier in the tested animal model. We found that nontransmissible strains can interfere the replication of fully transmissible strains when there is a species transmission barrier involved, as happened with the combination of a mouse (22L) and a human (sCJD) strain. However, this phenomenon seems to be strain dependent, since no interference was observed when the human strain coinoculated was vCJD. For the other combinations tested in this study, the results suggest that both strains replicate independently without effect on the replication of one over the other. It is common that the strain with more favorable conditions (e.g., a higher speed of disease development or the absence of a species barrier) ends being the only one detectable at the terminal stage of the disease. However, this does not exclude the replication of the least favored strain, leading to situations of the coexistence of prion strains. As a general conclusion, the outcome of prion coinfection is strongly dependent on the strain combination and the model utilized and is therefore difficult to predict. The coexistence of several prion strains may remain undetected if one of the strains has more favorable conditions to replicate in the host. The use of several models (such as a transgenic mouse expressing PrP from different species) to analyze field prion isolates is recommended to avoid this situation. The inference effect exerted by nonreplicative prion strains should be considered an interesting tool to advance in new therapeutic strategies for treating prion diseases; it may even be a proper therapeutic strategy.
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http://dx.doi.org/10.1128/JVI.01086-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258938PMC
December 2018

Protective Effect of Val-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease.

Emerg Infect Dis 2017 09;23(9):1522-1530

Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met) or valine (Val) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val Hu-PrP-positive humans with the emergence of new strain features.
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http://dx.doi.org/10.3201/eid2309.161948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572891PMC
September 2017

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

An assessment of the long-term persistence of prion infectivity in aquatic environments.

Environ Res 2016 Nov 1;151:587-594. Epub 2016 Sep 1.

Centro de Investigación en Sanidad Animal, CISA-INIA, Carretera Algete-El Casar S/n, Valdeolmos, 28130 Madrid, Spain. Electronic address:

The environment plays a key role in horizontal transmission of prion diseases, since prions are extremely resistant to classical inactivation procedures. In prior work, we observed the high stability of bovine spongiform encephalopathy (BSE) infectivity when these prions were incubated in aqueous media such as phosphate-buffered saline (PBS) or wastewater for nearly nine months. As a continuation of this experiment, the same samples were maintained in PBS or wastewater for five additional years and residual BSE infectivity was assessed in bovine PrP transgenic mice. Over this long time period (more than six years), BSE infectivity was reduced by three and one orders of magnitude in wastewater and PBS respectively. To rule out a possible agent specific effect, sheep scrapie prions were subjected to the same experimental protocol, using eight years as the experimental end-point. No significant reduction in scrapie infectivity was observed over the first nine months of wastewater incubation while PBS incubation for eight years only produced a two logarithmic unit reduction in infectivity. By contrast, the dynamics of PrP persistence was different, disappearing progressively over the first year. The long persistence of prion infectivity observed in this study for two different agents provides supporting evidence of the assumed high stability of these agents in aquatic environments and that environmental processes or conventional wastewater treatments with low retention times would have little impact on prion infectivity. These results could have great repercussions in terms of risk assessment and safety for animals and human populations.
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http://dx.doi.org/10.1016/j.envres.2016.08.031DOI Listing
November 2016

Reelin Expression in Creutzfeldt-Jakob Disease and Experimental Models of Transmissible Spongiform Encephalopathies.

Mol Neurobiol 2017 Oct 10;54(8):6412-6425. Epub 2016 Oct 10.

Molecular and Cellular Neurobiotechnology, Institute of Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, 08028, Barcelona, Spain.

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer's disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration.
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http://dx.doi.org/10.1007/s12035-016-0177-8DOI Listing
October 2017

Goat K-PrP polymorphic variant does not provide resistance to atypical scrapie in transgenic mice.

Vet Res 2016 Sep 22;47(1):96. Epub 2016 Sep 22.

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

Host prion (PrP) genotype is a major determinant for the susceptibility to prion diseases. The Q/K-PrP polymorphic variant provides goats and mice with high resistance against classical scrapie and bovine spongiform encephalopathy (BSE); yet its effect against atypical scrapie is unknown. Here, transgenic mice expressing the goat wild-type (wt) or the K-PrP variant were intracerebrally inoculated with several natural cases of atypical scrapie from sheep and goat and their susceptibility to the prion disease was determined. Goat wt and K-PrP transgenic mice were 100% susceptible to all the atypical scrapie isolates, showing similar survival times and almost identical disease phenotypes. The capacity of the K-PrP variant to replicate specifically the atypical scrapie strain as efficiently as the goat wt PrP, but not the classical scrapie or cattle-BSE as previously reported, further suggests the involvement of concrete areas of the host PrP in the strain-dependent replication of prions.
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http://dx.doi.org/10.1186/s13567-016-0380-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034450PMC
September 2016

The Priority position paper: Protecting Europe's food chain from prions.

Prion 2016 05;10(3):165-81

p Prionics , Zürich , Switzerland ;

Bovine spongiform encephalopathy (BSE) created a global European crisis in the 1980s and 90s, with very serious health and economic implications. Classical BSE now appears to be under control, to a great extent as a result of a global research effort that identified the sources of prions in meat and bone meal (MBM) and developed new animal-testing tools that guided policy. Priority ( www.prionpriority.eu ) was a European Union (EU) Framework Program 7 (FP7)-funded project through which 21 European research institutions and small and medium enterprises (SMEs) joined efforts between 2009 and 2014, to conduct coordinated basic and applied research on prions and prion diseases. At the end of the project, the Priority consortium drafted a position paper ( www.prionpriority.eu/Priority position paper) with its main conclusions. In the present opinion paper, we summarize these conclusions. With respect to the issue of re-introducing ruminant protein into the feed-chain, our opinion is that sustaining an absolute ban on feeding ruminant protein to ruminants is essential. In particular, the spread and impact of non-classical forms of scrapie and BSE in ruminants is not fully understood and the risks cannot be estimated. Atypical prion agents will probably continue to represent the dominant form of prion diseases in the near future in Europe. Atypical L-type BSE has clear zoonotic potential, as demonstrated in experimental models. Similarly, there are now data indicating that the atypical scrapie agent can cross various species barriers. More epidemiological data from large cohorts are necessary to reach any conclusion on the impact of its transmissibility on public health. Re-evaluations of safety precautions may become necessary depending on the outcome of these studies. Intensified searching for molecular determinants of the species barrier is recommended, since this barrier is key for important policy areas and risk assessment. Understanding the structural basis for strains and the basis for adaptation of a strain to a new host will require continued fundamental research, also needed to understand mechanisms of prion transmission, replication and how they cause nervous system dysfunction and death. Early detection of prion infection, ideally at a preclinical stage, also remains crucial for development of effective treatment strategies.
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http://dx.doi.org/10.1080/19336896.2016.1175801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981192PMC
May 2016

Involvement of PrP(C) in kainate-induced excitotoxicity in several mouse strains.

Sci Rep 2015 Jul 9;5:11971. Epub 2015 Jul 9.

1] Molecular and Cellular Neurobiotechnology, Institute of Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Barcelona, Spain [2] Department of Cell Biology, Universitat de Barcelona, Barcelona, Spain [3] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.

The cellular prion protein (PrP(C)) has been associated with a plethora of cellular functions ranging from cell cycle to neuroprotection. Mice lacking PrP(C) show an increased susceptibility to epileptic seizures; the protein, then, is neuroprotective. However, lack of experimental reproducibility has led to considering the possibility that other factors besides PrP(C) deletion, such as the genetic background of mice or the presence of so-called "Prnp flanking genes", might contribute to the reported susceptibility. Here, we performed a comparative analysis of seizure-susceptibility using characterized Prnp(+/+) and Prnp(0/0) mice of B6129, B6.129, 129/Ola or FVB/N genetic backgrounds. Our study indicates that PrP(C) plays a role in neuroprotection in KA-treated cells and mice. For this function, PrP(C) should contain the aa32-93 region and needs to be linked to the membrane. In addition, some unidentified "Prnp-flanking genes" play a role parallel to PrP(C) in the KA-mediated responses in B6129 and B6.129 Prnp(0/0) mice.
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http://dx.doi.org/10.1038/srep11971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648388PMC
July 2015

Effect of Q211 and K222 PRNP Polymorphic Variants in the Susceptibility of Goats to Oral Infection With Goat Bovine Spongiform Encephalopathy.

J Infect Dis 2015 Aug 26;212(4):664-72. Epub 2015 Feb 26.

Centro de Investigación en Sanidad Animal, Valdeolmos, Madrid, Spain.

Background: The prion protein-encoding gene (PRNP) is one of the major determinants for scrapie occurrence in sheep and goats. However, its effect on bovine spongiform encephalopathy (BSE) transmission to goats is not clear.

Methods: Goats harboring wild-type, R/Q211 or Q/K222 PRNP genotypes were orally inoculated with a goat-BSE isolate to assess their relative susceptibility to BSE infection. Goats were killed at different time points during the incubation period and after the onset of clinical signs, and their brains as well as several peripheral tissues were analyzed for the accumulation of pathological prion protein (PrP(Sc)) and prion infectivity by mouse bioassay.

Results: R/Q211 goats displayed delayed clinical signs compared with wild-type goats. Deposits of PrP(Sc) were detected only in brain, whereas infectivity was present in peripheral tissues too. In contrast, none of the Q/K222 goats showed any evidence of clinical prion disease. No PrP(Sc) accumulation was observed in their brains or peripheral tissues, but very low infectivity was detected in some tissues very long after inoculation (44-45 months).

Conclusions: These results demonstrate that transmission of goat BSE is genotype dependent, and they highlight the pivotal protective effect of the K222 PRNP variant in the oral susceptibility of goats to BSE.
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http://dx.doi.org/10.1093/infdis/jiv112DOI Listing
August 2015

Evidence for zoonotic potential of ovine scrapie prions.

Nat Commun 2014 Dec 16;5:5821. Epub 2014 Dec 16.

UMR INRA ENVT 1225, Interactions Hôtes Agents Pathogènes, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles, 31076 Toulouse, France.

Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie prions remains unknown. Mice genetically engineered to overexpress the human prion protein (tgHu) have emerged as highly relevant models for gauging the capacity of prions to transmit to humans. These models can propagate human prions without any apparent transmission barrier and have been used used to confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie prions transmit to several tgHu mice models with an efficiency comparable to that of cattle BSE. The serial transmission of different scrapie isolates in these mice led to the propagation of prions that are phenotypically identical to those causing sporadic CJD (sCJD) in humans. 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/10.1038/ncomms6821DOI Listing
December 2014

Prion and prion-like diseases in animals.

Virus Res 2015 Sep 29;207:82-93. Epub 2014 Nov 29.

Centro de Investigación en Sanidad Animal (CISA-INIA), 28130 Valdeolmos, Madrid, Spain. Electronic address:

Transmissible spongiform encephalopaties (TSEs) are fatal neurodegenerative diseases characterized by the aggregation and accumulation of the misfolded prion protein in the brain. Other proteins such as β-amyloid, tau or Serum Amyloid-A (SAA) seem to share with prions some aspects of their pathogenic mechanism; causing a variety of so called prion-like diseases in humans and/or animals such as Alzheimer's, Parkinson's, Huntington's, Type II diabetes mellitus or amyloidosis. The question remains whether these misfolding proteins have the ability to self-propagate and transmit in a similar manner to prions. In this review, we describe the prion and prion-like diseases affecting animals as well as the recent findings suggesting the prion-like transmissibility of certain non-prion proteins.
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http://dx.doi.org/10.1016/j.virusres.2014.11.026DOI Listing
September 2015

Transmission characteristics of variably protease-sensitive prionopathy.

Emerg Infect Dis 2014 Dec;20(12):2006-14

Variably protease-sensitive prionopathy (VPSPr), a recently identified and seemingly sporadic human prion disease, is distinct from Creutzfeldt-Jakob disease (CJD) but shares features of Gerstmann-Sträussler-Scheinker disease (GSS). However, contrary to exclusively inherited GSS, no prion protein (PrP) gene variations have been detected in VPSPr, suggesting that VPSPr might be the long-sought sporadic form of GSS. The VPSPr atypical features raised the issue of transmissibility, a prototypical property of prion diseases. We inoculated VPSPr brain homogenate into transgenic mice expressing various levels of human PrP (PrPC). On first passage, 54% of challenged mice showed histopathologic lesions, and 34% harbored abnormal PrP similar to that of VPSPr. Surprisingly, no prion disease was detected on second passage. We concluded that VPSPr is transmissible; thus, it is an authentic prion disease. However, we speculate that normal human PrPC is not an efficient conversion substrate (or mouse brain not a favorable environment) and therefore cannot sustain replication beyond the first passage.
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http://dx.doi.org/10.3201/eid2012.140548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257788PMC
December 2014

Elements modulating the prion species barrier and its passage consequences.

PLoS One 2014 7;9(3):e89722. Epub 2014 Mar 7.

UMR INRA-ENVT 1225, Interactions Hôte Agent Pathogène, École Nationale Vétérinaire de Toulouse, France.

The specific characteristics of Transmissible Spongiform Encephalopathy (TSE) strains may be altered during passage across a species barrier. In this study we investigated the biochemical and biological characteristics of Bovine Spongiform Encephalopathy (BSE) after transmission in both natural host species (cattle, sheep, pigs and mice) and in transgenic mice overexpressing the corresponding cellular prion protein (PrPC) in comparison with other non-BSE related prions from the same species. After these passages, most features of the BSE agent remained unchanged. BSE-derived agents only showed slight modifications in the biochemical properties of the accumulated PrPSc, which were demonstrated to be reversible upon re-inoculation into transgenic mice expressing bovine-PrPC. Transmission experiments in transgenic mice expressing bovine, porcine or human-PrP revealed that all BSE-derived agents were transmitted with no or a weak transmission barrier. In contrast, a high species barrier was observed for the non-BSE related prions that harboured an identical PrP amino acid sequence, supporting the theory that the prion transmission barrier is modulated by strain properties (presumably conformation-dependent) rather than by PrP amino acid sequence differences between host and donor. As identical results were observed with prions propagated either in natural hosts or in transgenic mouse models, we postulate that the species barrier and its passage consequences are uniquely governed by the host PrPC sequence and not influenced by other host genetic factors. The results presented herein reinforce the idea that the BSE agent is highly promiscuous, infecting other species, maintaining its properties in the new species, and even increasing its capabilities to jump to other species including humans. These data are essential for the development of an accurate risk assessment for BSE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089722PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946430PMC
December 2014