Development and characterization of transgenic mouse models of chronic wasting disease: A prion disease of deer and elk

Studies of chronic wasting disease (CWD), a prion disease of deer and elk, have been inhibited by the cost of housing deer and elk in prion free pastures for the approximately two years necessary for these animals to develop disease. Studies of CWD have also been hampered by the difficulty of propagating CWD prions in other experimental hosts, an effect called the species barrier. Here we detail the production and characterization of transgenic mice expressing the cervid prion protein (CerPrP) which are susceptible to CWD after incubations as low as 160 days. Transgenic CerPrP mice inoculated with CWD prions demonstrate neuropathological characteristics similar to CWD in cervids, including localized spongiform degeneration and florid amyloid plaques.; Polymorphisms in the prion protein gene (Prnp) affect susceptibility to prion disease. Human Prnp is polymorphic at codon 129 (M/V) which is an important determinant for susceptibility in human prion diseases. Elk Prnp is polymorphic at codon 132 (M/L), which is analogous to human 129. Transgenic mice expressing cervid Prnp with the leucine polymorphism at codon 132 are protected against prion disease following inoculations with CWD prions.; Central to the current understanding of how prions are propagated is the hypothesized involvement of a ligand, denoted protein X, which assists in the conversion of PrPC to PrPSc. To directly test the involvement of protein X we generated transgenic mice expressing a chimeric PrP construct, referred to as MCerB+C, containing mouse residues predicted to associate with mouse protein X and cervid residues predicted to interact with PrPSc from cervids with CWD. MCerB+C was designed to confer efficient propagation of CWD prions, however transgenic mice expressing MCerB+C PrP were resistant to CWD prions and unexpectedly susceptible to mouse prions. Although a species barrier inhibits the susceptibility of CerPrP transgenic mice to mouse prions, surprisingly the passage of mouse prions through MCerB+C transgenic mice conferred on them the ability to infect CerPrP transgenic mice. The results of these transgenic studies provide new information about the molecular mechanisms of prion propagation in the context of the protein X model and underscore the importance of PrP primary structure on strain characteristics.