title: Emergence of two prion subtypes in ovine PrP transgenic mice infected with human MM2-cortical Creutzfeldt-Jakob disease prions.
abstract: BACKGROUND
  Mammalian prions are proteinaceous pathogens responsible for a broad range of fatal neurodegenerative diseases in humans and animals. These diseases can occur spontaneously, such as Creutzfeldt-Jakob disease (CJD) in humans, or be acquired or inherited. Prions are primarily formed of macromolecular assemblies of the disease-associated prion protein PrP(Sc), a misfolded isoform of the host-encoded prion protein PrP(C). Within defined host-species, prions can exist as conformational variants or strains. Based on both the M/V polymorphism at codon 129 of PrP and the electrophoretic signature of PrP(Sc) in the brain, sporadic CJD is classified in different subtypes, which may encode different strains. A transmission barrier, the mechanism of which remains unknown, limits prion cross-species propagation. To adapt to the new host, prions have the capacity to 'mutate' conformationally, leading to the emergence of a variant with new biological properties. Here, we transmitted experimentally one rare subtype of human CJD, designated cortical MM2 (129 MM with type 2 PrP(Sc)), to transgenic mice overexpressing either human or the VRQ allele of ovine PrP(C).
  
  
  RESULTS
  In marked contrast with the reported absence of transmission to knock-in mice expressing physiological levels of human PrP, this subtype transmitted faithfully to mice overexpressing human PrP, and exhibited unique strain features. Onto the ovine PrP sequence, the cortical MM2 subtype abruptly evolved on second passage, thereby allowing emergence of a pair of strain variants with distinct PrP(Sc) biochemical characteristics and differing tropism for the central and lymphoid tissues. These two strain components exhibited remarkably distinct replicative properties in cell-free amplification assay, allowing the 'physical' cloning of the minor, lymphotropic component, and subsequent isolation in ovine PrP mice and RK13 cells.
  
  
  CONCLUSIONS
  Here, we provide in-depth assessment of the transmissibility and evolution of one rare subtype of sporadic CJD upon homologous and heterologous transmission. The notion that the environment or matrix where replication is occurring is key to the selection and preferential amplification of prion substrain components raises new questions on the determinants of prion replication within and between species. These data also further interrogate on the interplay between animal and human prions.
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.
authors: Jérôme
authors: J
authors: Chapuis
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.
authors: Mohammed
authors: M
authors: Moudjou
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.
authors: Fabienne
authors: F
authors: Reine
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.
authors: Laetitia
authors: L
authors: Herzog
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.
authors: Emilie
authors: E
authors: Jaumain
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.
authors: Céline
authors: C
authors: Chapuis
authors: Neurobiology Laboratory, Biochemistry and Molecular Biology Department, Hôpitaux de Lyon, Lyon, France.|University of Lyon 1, CNRS UMR5292, INSERM U1028, BioRan, Lyon, France.
authors: Isabelle
authors: I
authors: Quadrio
authors: Neurology Department, Centre Hospitalo-Universitaire, Bourg en Bresse, France.
authors: Jacques
authors: J
authors: Boulliat
authors: Neurobiology Laboratory, Biochemistry and Molecular Biology Department, Hôpitaux de Lyon, Lyon, France.|University of Lyon 1, CNRS UMR5292, INSERM U1028, BioRan, Lyon, France.
authors: Armand
authors: A
authors: Perret-Liaudet
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.
authors: Michel
authors: M
authors: Dron
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.
authors: Hubert
authors: H
authors: Laude
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France.
authors: Human
authors: H
authors: Rezaei
authors: INRA (Institut National de la Recherche Agronomique), UR892, Virologie Immunologie Moléculaires, F-78350, Jouy-en-Josas, France. vincent.beringue@jouy.inra.fr.
authors: Vincent
authors: V
authors: Béringue
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology*; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000473:pathology / Q000635:transmission; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011328:Prions / Q000145:classification / Q000235:genetics*; D017510:Protein Folding; D012756:Sheep; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013552:Swine; D014162:Transfection
chemical_list: D011328:Prions