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 Prnpa and Prnpb polymorphisms (which produced the proteins PrPa and PrPb, 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 Prnpa and Prnpb mice can primarily be explained on the basis of faster or more efficient aggregation of PrPa. In addition, and more importantly, we found that the faithful propagation of strains in Prnpb mice can be explained by the ability of PrPb to adopt a wider range of conformations. This adaptability allows PrPb to successfully propagate the structural features of a seed. In contrast, Prnpa mice revert PrPb strains into PrPa-type strains, and overall they have a narrower distribution of incubation periods. This can be explained by PrPa 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. © 2013 Landes Bioscience.