Implications of prion polymorphisms

Abstract

The sequence of a host's prion protein (PrP) can affect that host's susceptibility to prion disease and is the primary basis for the species barrier to transmission. Yet within many species, polymorphisms of the prion protein gene (Prnp) exist, each of which can further affect susceptibility or influence incubation period, pathology and phenotype. As strains are defined by these features (incubation period, pathology, phenotype), polymorphisms may also lead to the preferential propagation or generation of certain strains. In our recent study of the mouse Prnp(a) and Prnp(b) polymorphisms (which produced the proteins PrP(a) and PrP(b), respectively), we found differences in aggregation tendency, strain adaptability and conformational variability. Comparing our in vitro data with that of in vivo studies, we found that differing incubation periods between Prnp(a) and Prnp(b) mice can primarily be explained on the basis of faster or more efficient aggregation of PrP(a). In addition, and more importantly, we found that the faithful propagation of strains in Prnp(b) mice can be explained by the ability of PrP(b) to adopt a wider range of conformations. This adaptability allows PrP(b) to successfully propagate the structural features of a seed. In contrast, Prnp(a) mice revert PrP(b) strains into PrP(a) -type strains, and overall they have a narrower distribution of incubation periods. This can be explained by PrP(a) having fewer preferred conformations. We propose that Prnp polymorphisms are one route by which certain prion strains may preferentially propagate. This has significant implications for prion disease, chronic wasting disease (CWD) in particular, as it is spreading through North America. Deer which are susceptible to CWD also carry polymorphisms which influence their susceptibility. If these polymorphisms also preferentially allow strain diversification and propagation, this may accelerate the crossing of species barriers and propagation of the disease up the food chain.

Keywords: adaptation; aggregation; amyloid; kinetics; mouse; polymorphism; prion; propagation; species barrier; strain.

Figure 1.Incubation period of Prnp^a and Prnp^b mice infected with scrapie or BSE. (A) Mean incubation period (days) for transmission of spongiform encephalopathy to Prnp^a (open circles) and Prnp^b (open squares) mice from 7 dairy cattle sources, 1 sheep with natural scrapie, 3 cats and 1 sheep, 1 goat and 1 pig that developed clinical disease after experimental infection with BSE (data taken from Bruce et al.¹⁰). (B) Mean incubation period (days) following infection of Prnp^a and Prnp^b mice with 14 scrapie/BSE mouse-adapted strains, 8 isolated from Prnp^a (empty circles) and 6 from Prnp^b (filled squares) mice (data taken from Bruce et al.⁷). (C) Mean incubation period (days) for infection of Prnp^a and Prnp^b mice with 22C, 22A, 79A, and 79V strains (data taken from Bruce et al.⁷). The mean for each set of data are represented by the horizontal line.