title: The elk PRNP codon 132 polymorphism controls cervid and scrapie prion propagation.
abstract: The elk prion protein gene (PRNP) encodes either methionine (M) or leucine (L) at codon 132, the L132 allele apparently affording protection against chronic wasting disease (CWD). The corresponding human codon 129 polymorphism influences the host range of bovine spongiform encephalopathy (BSE) prions. To fully address the influence of this cervid polymorphism on CWD pathogenesis, we created transgenic (Tg) mice expressing cervid PrPC with L at residue 132, referred to as CerPrPC-L132, and compared the transmissibility of CWD prions from elk of defined PRNP genotypes, namely homozygous M/M or L/L or heterozygous M/L, in these Tg mice with previously described Tg mice expressing CerPrPC-M132, referred to as Tg(CerPrP) mice. While Tg(CerPrP) mice were consistently susceptible to CWD prions from elk of all three genotypes, Tg(CerPrP-L132) mice uniformly failed to develop disease following challenge with CWD prions. In contrast, SSBP/1 sheep scrapie prions transmitted efficiently to both Tg(CerPrP) and Tg(CerPrP-L132) mice. Our findings suggest that the elk 132 polymorphism controls prion susceptibility at the level of prion strain selection and that cervid PrP L132 severely restricts propagation of CWD prions. We speculate that the L132 polymorphism results in less efficient conversion of CerPrPC-L132 by CWD prions, an effect that is overcome by the SSBP/1 strain. Our studies show the accumulation of subclinical levels of CerPrPSc in aged asymptomatic CWD-inoculated Tg(CerPrP-L132) mice and also suggests the establishment of a latent infection state in apparently healthy elk expressing this seemingly protective allele.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA.
authors.forename: Kristi M
authors.initials: KM
authors.lastname: Green
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA.
authors.forename: Shawn R
authors.initials: SR
authors.lastname: Browning
authors.affiliation: Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Tanya S
authors.initials: TS
authors.lastname: Seward
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, Laramie, WY, USA.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Jewell
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA.
authors.forename: Dana L
authors.initials: DL
authors.lastname: Ross
authors.affiliation: Transgenic Facility, University of Kentucky, Lexington, KY, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Green
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, Laramie, WY, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Williams
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Hoover
authors.affiliation: Department of Neurology, University of Kentucky, Lexington, KY, USA.|Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA.|Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
mesh_terms: D000818:Animals; D003062:Codon; D003670:Deer; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D051379:Mice; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic; D018621:PrPC Proteins / Q000235:genetics* / Q000302:isolation & purification; D017096:Prion Diseases / Q000635:transmission*; D011328:Prions / Q000378:metabolism*; D012608:Scrapie; D034081:Wasting Disease, Chronic / Q000235:genetics* / Q000635:transmission*
chemical_list: D003062:Codon; D018621:PrPC Proteins; D011328:Prions