Prion-type dependent deposition of PRNP allelic products in heterozygous sheep

Susceptibility or resistance to prion infection in humans and animals depends on single prion protein (PrP) amino acid substitutions in the host, but the agent's modulating role has not been well investigated. Compared to disease incubation times in wild type homozygous ARQ/ARQ sheep, scrapie susceptibility is reduced to near resistance in ARR/ARR animals while it is strongly enhanced in VRQ/VRQ carriers. Heterozygous ARR/VRQ animals exhibit delayed incubation periods. In BSE infection the polymorphism effect is quite different, though the ARR allotype remains the least susceptible. In this study, PrP allotype composition in protease resistant prion protein (PrP(res)) from brain of heterozygous ARR/VRQ scrapie infected sheep was compared with that of BSE infected sheep with similar genotype. The triplex-Western blotting technique was used to estimate the two allotype PrP fractions in PrP(res) material from BSE infected ARR/VRQ sheep. PrP(res) in BSE contained equimolar amounts of VRQ- and ARR-PrP which contrasts with the excess (>95%) VRQ-PrP fraction found in scrapie. This is evidence that TSE agent properties alone, perhaps structural aspects of prions (such as PrP amino acid sequence variants and PrP conformational state) determine the polymorphic dependence of the PrP(Sc) accumulation process in prion formation as well as the disease associated phenotypic expressions in the host.