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

ABSTRACT: Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrP^C into PrP^Sc. Structurally distinct PrP^Sc conformers can give rise to multiple prion strains. Constrained interactions between PrP^C and different PrP^Sc strains can in turn lead to certain PrP^Sc (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^C. 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^C. While breeding true in mice expressing PrP^C at near physiological levels, scrapie prions evolve consistently towards different strain components in mice beyond a certain threshold of PrP^C overexpression. Our results support the view that PrP^C gene dosage can influence prion evolution on homotypic transmission.

SUBMITTER: Le Dur A

PROVIDER: S-EPMC5264111 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Le Dur Annick A Laï Thanh Lan TL Stinnakre Marie-George MG Laisné Aude A Chenais Nathalie N Rakotobe Sabine S Passet Bruno B Reine Fabienne F Soulier Solange S Herzog Laetitia L Tilly Gaëlle G Rézaei Human H Béringue Vincent V Vilotte Jean-Luc JL Laude Hubert H

Nature communications 20170123

Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrPC into PrPSc. Structurally distinct PrPSc conformers can give rise to multiple prion strains. Constrained interactions between PrPC and different PrPSc strains can in turn lead to certain PrPSc (sub)populations being selected for cross-species transmission, or even produce mutation-like ...[more]

PMID: 28112164

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Project description:Transgenic (Tg) mice expressing chimeras of mouse and human prion proteins (PrPs) have shorter incubation periods for Creutzfeldt-Jakob disease (CJD) prions than mice expressing full-length human PrP. Increasing the sequence similarity of the chimeric PrP to mouse PrP, by reverting human residues to mouse, resulted in a Tg line, denoted Tg22372, which was susceptible to sporadic (s) CJD prions in approximately 110 days.Mice expressing chimeric mouse/human PrP transgenes were produced. The mice were inoculated intracerebrally with extracts prepared from the brains of patients who died of CJD. Onset of neurological dysfunction marked the end of the incubation time. After sacrifice of the Tg mice, their brains were analyzed for PrP(Sc) and neuropathological changes.Reversion of 1 additional residue (M111V) resulted in a new Tg line, termed Tg1014, susceptible to sCJD prions in approximately 75 days. Tg1014 mice also have shorter incubation periods for variant (v) CJD prions, providing a more tractable model for studying this prion strain. Transmission of vCJD prions to Tg1014 mice resulted in 2 different strains, determined by neuropathology and biochemical analysis, which correlated with the length of the incubation time. One strain had the biochemical, neuropathological, and transmission characteristics, including longer incubation times, of the inoculated vCJD strain; the second strain produced a phenotype resembling that of sCJD prions including relatively shorter incubation periods. Mice with intermediate incubation periods for vCJD prions had a mixture of the 2 strains. Both strains were serially transmitted in Tg1014 mice, which led to further reduction in incubation periods. Conversion of vCJD-like to sCJD-like strains was favored in Tg1014 mice more than in the Tg22372 line. The single amino acid difference therefore appears to offer selective pressure for propagation of the sCJD-like strain.These 2 Tg mouse lines provide relatively rapid models to study human prion diseases as well as the evolution of human prion strains.

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

Publications

Divergent prion strain evolution driven by PrP<sup>C</sup> expression level in transgenic mice.

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