Role of Deformed Templating in Prion Mutation

The last several years have marked a noticeable shift in our perception of the prion replication mechanism. According to the ‘‘cloud’ ’ hypothesis, pools of infectious isoform of prion protein (PrPSc) within individual strains or isolates are intrinsically heterogeneous; the heterogeneity presumably arises due to spontaneous variation in PrPSc structure [1,2]. Upon changes in the replication environment, minor variants that fit best to replicate in the new environment receive selective advantages. Consistent with this view, a growing number of studies have highlighted the fact that prion strains exhibit high levels of conformational plasticity and are subject to transformation when exposed to new replication environments. Drug-resistant prions were found to emerge in cultured cells following treatment with prion inhibitors swainsonine or quinacrine [2,3]. Studies by Weissmann’s group showed that cloned prion strains accumulate PrPSc variants quite quickly, presumably due to ongoing processes of spontaneous ‘‘mutations’ ’ of PrPSc structure [2]. What are the origins of strain mutation and how do prions mutate? According to the ‘‘cloud’ ’ hypothesis, changes in replication environment might give selective advantage to minor PrPSc variants that are already present in the PrPSc pool [1]. However, the origin of minor variants is not clearly specified (Figure 1A)