title: Mutated but Not Deleted Ovine PrP(C) N-Terminal Polybasic Region Strongly Interferes with Prion Propagation in Transgenic Mice.
abstract: Mammalian prions are proteinaceous infectious agents composed of misfolded assemblies of the host-encoded, cellular prion protein (PrP). Physiologically, the N-terminal polybasic region of residues 23 to 31 of PrP has been shown to be involved in its endocytic trafficking and interactions with glycosaminoglycans or putative ectodomains of membrane-associated proteins. Several recent reports also describe this PrP region as important for the toxicity of mutant prion proteins and the efficiency of prion propagation, both in vitro and in vivo. The question remains as to whether the latter observations made with mouse PrP and mouse prions would be relevant to other PrP species/prion strain combinations given the dramatic impact on prion susceptibility of minimal amino acid substitutions and structural variations in PrP. Here, we report that transgenic mouse lines expressing ovine PrP with a deletion of residues 23 to 26 (KKRP) or mutated in this N-terminal region (KQHPH instead of KKRPK) exhibited a variable, strain-dependent susceptibility to prion infection with regard to the proportion of affected mice and disease tempo relative to findings in their wild-type counterparts. Deletion has no major effect on 127S scrapie prion pathogenesis, whereas mutation increased by almost 3-fold the survival time of the mice. Deletion marginally affected the incubation time of scrapie LA19K and ovine bovine spongiform encephalopathy (BSE) prions, whereas mutation caused apparent resistance to disease.
  
  
  OBJECTIVE
  Recent reports suggested that the N-terminal polybasic region of the prion protein could be a therapeutic target to prevent prion propagation or toxic signaling associated with more common neurodegenerative diseases such as Alzheimer's disease. Mutating or deleting this region in ovine PrP completes the data previously obtained with the mouse protein by identifying the key amino acid residues involved.
authors.affiliation: UMR1313 Génétique Animale et Biologie Intégrative, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Manal
authors.initials: M
authors.lastname: Khalifé
authors.affiliation: UR892 Virologie Immunologie Moléculaires, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Reine
authors.affiliation: UR892 Virologie Immunologie Moléculaires, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Paquet-Fifield
authors.affiliation: UMR1313 Génétique Animale et Biologie Intégrative, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Johan
authors.initials: J
authors.lastname: Castille
authors.affiliation: UR892 Virologie Immunologie Moléculaires, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Herzog
authors.affiliation: UMR1313 Génétique Animale et Biologie Intégrative, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Marthe
authors.initials: M
authors.lastname: Vilotte
authors.affiliation: UR892 Virologie Immunologie Moléculaires, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Moudjou
authors.affiliation: UMR1313 Génétique Animale et Biologie Intégrative, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Moazami-Goudarzi
authors.affiliation: UMR1313 Génétique Animale et Biologie Intégrative, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Samira
authors.initials: S
authors.lastname: Makhzami
authors.affiliation: UMR1313 Génétique Animale et Biologie Intégrative, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Passet
authors.affiliation: UMR1225, Ecole Nationale Vétérinaire Toulouse-INRA Institut National de la Recherche Agronomique, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Andréoletti
authors.affiliation: UR892 Virologie Immunologie Moléculaires, Institut National de la Recherche Agronomique, Jouy-en-Josas, France UMR1225, Ecole Nationale Vétérinaire Toulouse-INRA Institut National de la Recherche Agronomique, Toulouse, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Vilette
authors.affiliation: UR892 Virologie Immunologie Moléculaires, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Laude
authors.affiliation: UR892 Virologie Immunologie Moléculaires, Institut National de la Recherche Agronomique, Jouy-en-Josas, France vincent.beringue@jouy.inra.fr jean-luc.vilotte@jouy.inra.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Béringue
authors.affiliation: UMR1313 Génétique Animale et Biologie Intégrative, Institut National de la Recherche Agronomique, Jouy-en-Josas, France vincent.beringue@jouy.inra.fr jean-luc.vilotte@jouy.inra.fr.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Vilotte
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D018621:PrPC Proteins / Q000235:genetics* / Q000378:metabolism*; D017096:Prion Diseases / Q000473:pathology*; D017384:Sequence Deletion; D012756:Sheep
chemical_list: D050505:Mutant Proteins; D018621:PrPC Proteins