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 PrP C with L at residue 132, referred to as CerPrP C -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 CerPrP C -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 CerPrP C -L132 by CWD prions, an effect that is overcome by the SSBP/1 strain. Our studies show the accumulation of subclinical levels of CerPrP Sc 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.

Prion agent diversity and species barrier

“…Two other 'absolute' species barriers in mice have recently been broken. Expression of mink PrP [206] and cervid PrP [30,82,113,117,134,188] in transgenic mice render them susceptible to TME and CWD, respectively. It is noteworthy that the use of transgenic mice overexpressing mouse PrP C also allowed the propagation of the CWD agent [179].…”

“…This apparent lack of species barrier after homotypic transmission -i.e. when the host expresses a PrP gene identical to that of the infecting species -has led to the development of a long list of mice transgenic for sheep [60,197,203], bovine [20,41,48,175], human [5,22,113,190], cervid [30,82,113,117,134,188] and mink [206] PrP. Most of such lines were obtained by additional transgenesis, and have an endogenous PrP null (PrP 0/0 ) background, in order to avoid any interfering effect of the resident murine PrP gene [39,190].…”

“…A methionine/leucine polymorphism at codon 132 (site corresponding to codon 129 in humans) of elk PrP gene influences the susceptibility to CWD. Sick animals homozygous for Met at codon 132 are overrepresented [142], an effect reproduced in transgenic mice [82]. The disease can spread horizontally and the attack rate can be important in farmed cervids (up to 95%).…”

“…Whether this finding reflects different strains or simply the propagation of the same strain on two distinct PrP genotypes is unclear. However the marked resistance to CWD of mice transgenic for elk prion protein with L132 allele [82] might argue for the presence of another strain. Over the last few years, several transgenic mouse lines have been developed that express either elk or mule-deer PrP [30,113,117,188], with polymorphisms at codon 132 or 96 [82,134].…”

“…However the marked resistance to CWD of mice transgenic for elk prion protein with L132 allele [82] might argue for the presence of another strain. Over the last few years, several transgenic mouse lines have been developed that express either elk or mule-deer PrP [30,113,117,188], with polymorphisms at codon 132 or 96 [82,134]. It should be noted that mice expressing glycine at PrP residue 96 were fairly susceptible to oral infection by the CWD agent [194], or when the transgene was not overexpressed [134].…”