title: Prion strain mutation determined by prion protein conformational compatibility and primary structure.
abstract: Prions are infectious proteins composed of the abnormal disease-causing isoform PrPSc, which induces conformational conversion of the host-encoded normal cellular prion protein PrPC to additional PrPSc. The mechanism underlying prion strain mutation in the absence of nucleic acids remains unresolved. Additionally, the frequency of strains causing chronic wasting disease (CWD), a burgeoning prion epidemic of cervids, is unknown. Using susceptible transgenic mice, we identified two prevalent CWD strains with divergent biological properties but composed of PrPSc with indistinguishable biochemical characteristics. Although CWD transmissions indicated stable, independent strain propagation by elk PrPC, strain coexistence in the brains of deer and transgenic mice demonstrated unstable strain propagation by deer PrPC. The primary structures of deer and elk prion proteins differ at residue 226, which, in concert with PrPSc conformational compatibility, determines prion strain mutation in these cervids.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky Medical Center, Lexington, KY 40536, USA.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Angers
authors.forename: Hae-Eun
authors.initials: HE
authors.lastname: Kang
authors.forename: Dana
authors.initials: D
authors.lastname: Napier
authors.forename: Shawn
authors.initials: S
authors.lastname: Browning
authors.forename: Tanya
authors.initials: T
authors.lastname: Seward
authors.forename: Candace
authors.initials: C
authors.lastname: Mathiason
authors.forename: Aru
authors.initials: A
authors.lastname: Balachandran
authors.forename: Debbie
authors.initials: D
authors.lastname: McKenzie
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilla
authors.forename: Claudio
authors.initials: C
authors.lastname: Soto
authors.forename: Jean
authors.initials: J
authors.lastname: Jewell
authors.forename: Catherine
authors.initials: C
authors.lastname: Graham
authors.forename: Edward A
authors.initials: EA
authors.lastname: Hoover
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D003670:Deer; D004198:Disease Susceptibility; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics; D018620:PrPSc Proteins / Q000032:analysis / Q000737:chemistry* / Q000235:genetics / Q000472:pathogenicity; D011487:Protein Conformation; D017510:Protein Folding; D012641:Selection, Genetic; D012692:Serial Passage; D013045:Species Specificity; D034081:Wasting Disease, Chronic / Q000473:pathology / Q000635:transmission
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins
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