Elements Modulating the Prion Species Barrier and Its Passage Consequences

Torres, Juan María; Espinosa, Juan Carlos; Aguilar‐Calvo, Patricia; Herva, María-Eugenia; Relaño-Ginés, Aroa; Villa-Diaz, Ana; Morales, Mónica; Parra, Beatriz; Alamillo, Elia; Brun, Alejandro; Castilla, Joaquı́n; Molina, Susana; Hawkins, Steve; Andréoletti, Olivier

doi:10.1371/journal.pone.0089722

Cited by 49 publications

(75 citation statements)

References 41 publications

(54 reference statements)

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“…These unexpected vCJD transmission properties were subsequently confirmed using independently produced TgBoPrP (50,51). Confirming the shared properties of BSE/vCJD prions, the transmission profile of vCJD in Tg(HuPrP) and Tg(BoPrP) corresponded to that of BSE prions previously passaged in Tg(HuPrP) mice (51). The overlapping denaturation profiles of PrP Sc in the brains of diseased cattle and humans (52,53) are consistent with shared conformations of vCJD and BSE prions, which is also in accordance with NAPA.…”

Section: Discussionmentioning

confidence: 69%

“…In contrast, the preferential transmission of human vCJD prions to Tg mice expressing ancestral bovine PrP C [Tg(BoPrP)] without an obvious transmission barrier, producing neuropathological and PrP Sc molecular profiles corresponding to BSE, was equally surprising and at odds with adaptive prion transmission (46). These unexpected vCJD transmission properties were subsequently confirmed using independently produced TgBoPrP (50,51). Confirming the shared properties of BSE/vCJD prions, the transmission profile of vCJD in Tg(HuPrP) and Tg(BoPrP) corresponded to that of BSE prions previously passaged in Tg(HuPrP) mice (51).…”

Section: Discussionmentioning

confidence: 99%

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Prion replication without host adaptation during interspecies transmissions

Bian

Khaychuk

Angers

et al. 2017

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

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Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrPC) to selectively propagate optimized prion conformations from larger ensembles generated in the species of origin. Here we describe an alternate replicative process, termed nonadaptive prion amplification (NAPA), in which dominant conformers bypass this requirement during particular interspecies transmissions. To model susceptibility of horses to prions, we produced transgenic (Tg) mice expressing cognate PrPC. Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPCconversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPCwas similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPCfrom the species of prion origin, demonstrating that transmission barrier eradication of the originating prions was ephemeral and adaptation superficial in TgEq and TgD. Horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrPCalso failed to infect TgEq but retained tropism for wild-type mice. Concordant patterns of neuropathology and prion deposition in susceptible mice infected with NAPA prions and the corresponding prion of origin confirmed preservation of strain properties. The comparable responses of both prion types to guanidine hydrochloride denaturation indicated this occurs because NAPA precludes selection of novel prion conformations. Our findings provide insights into mechanisms regulating interspecies prion transmission and a framework to reconcile puzzling epidemiological features of certain prion disorders.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Prion replication without host adaptation during interspecies transmissions

Bian

Khaychuk

Angers

et al. 2017

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

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“…Crude brain homogenates [10 % (w/v)] were prepared from diseased mice inoculated with spontaneously generated ovrecPrP(25-233)-amyloid and used for a second passage into the same mouse line. 65 PrP Sc in the brains of animals was detected by digestion of 10 % brain homogenates with 50 mg/ ml PK (recombinant grade; Roche Applied Science) for 2 h at 37 C followed by Western blot analysis.…”

Section: Mouse Bioassaymentioning

confidence: 99%

Progress towards structural understanding of infectious sheep PrP-amyloid

Müller

Brener

Andréoletti

et al. 2014

Prion

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The still elusive structural difference of non-infectious and infectious amyloid of the mammalian prion protein (PrP) is a major pending milestone in understanding protein-mediated infectivity in neurodegenerative diseases. Preparations of PrP-amyloid proven to be infectious have never been investigated with a high-resolution technique. All available models to date have been based on low-resolution data. Here, we establish protocols for the preparation of infectious samples of full-length recombinant (rec) PrP-amyloid in NMR-sufficient amounts by spontaneous fibrillation and seeded fibril growth from brain extract. We link biological and structural data of infectious recPrP-amyloid, derived from bioassays, atomic force microscopy, and solid-state NMR spectroscopy. Our data indicate a semi-mobile N-terminus, some residues with secondary chemical shifts typical of a-helical secondary structure in the middle part between »115 to »155, and a distinct b-sheet core C-terminal of residue »155. These findings are not in agreement with all current models for PrP-amyloid. We also provide evidence that samples seeded from brain extract may not differ in the overall arrangement of secondary structure elements, but rather in the flexibility of protein segments outside the b-core region. Taken together, our protocols provide an essential basis for the high-resolution characterization of non-infectious and infectious PrP-amyloid in the near future.

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“…The biological determinants of the prion species barrier are not well understood. Amino acid sequence similarity between the infectious PrP TSE and the host PrP C can strongly influence whether conversion takes place [3][4][5] , but remains insufficient to explain all prion transmission events observed in vivo 6,7 .…”

Section: Introductionmentioning

confidence: 99%

Assessing Transmissible Spongiform Encephalopathy Species Barriers with an <em>In Vitro</em> Prion Protein Conversion Assay

Johnson

Carlson

Morawski

et al. 2015

JoVE

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Studies to understanding interspecies transmission of transmissible spongiform encephalopathies (TSEs, prion diseases) are challenging in that they typically rely upon lengthy and costly in vivo animal challenge studies. A number of in vitro assays have been developed to aid in measuring prion species barriers, thereby reducing animal use and providing quicker results than animal bioassays. Here, we present the protocol for a rapid in vitro prion conversion assay called the conversion efficiency ratio (CER) assay. In this assay cellular prion protein (PrP C ) from an uninfected host brain is denatured at both pH 7.4 and 3.5 to produce two substrates. When the pH 7.4 substrate is incubated with TSE agent, the amount of PrP C that converts to a proteinase K (PK)-resistant state is modulated by the original host's species barrier to the TSE agent. In contrast, PrP C in the pH 3.5 substrate is misfolded by any TSE agent. By comparing the amount of PK-resistant prion protein in the two substrates, an assessment of the host's species barrier can be made. We show that the CER assay correctly predicts known prion species barriers of laboratory mice and, as an example, show some preliminary results suggesting that bobcats (Lynx rufus) may be susceptible to whitetailed deer (Odocoileus virginianus) chronic wasting disease agent. Video LinkThe video component of this article can be found at

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Elements Modulating the Prion Species Barrier and Its Passage Consequences

Cited by 49 publications

References 41 publications

Prion replication without host adaptation during interspecies transmissions

Prion replication without host adaptation during interspecies transmissions

Progress towards structural understanding of infectious sheep PrP-amyloid

Assessing Transmissible Spongiform Encephalopathy Species Barriers with an <em>In Vitro</em> Prion Protein Conversion Assay

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