Previous studies established that prion disease with unique strain-specific phenotypes could be induced by in vitro-formed recombinant PrP (rPrP) fibrils with structures different from that of authentic prions, or PrP^Sc. To explain the etiology of prion diseases, new mechanism proposed that in animals the transition from rPrP fibrils to PrP^Sc consists of two main steps: the first involves fibril-induced formation of atypical PrPres, a self-replicating but clinically silent state, and the second consists of atypical PrPres-dependent formation of PrP^Sc via rare deformed templating events.

In the current study, atypical PrPres with characteristics similar to those of brain-derived atypical PrPres was generated in vitro. Upon inoculation into animals, in vitro-generated atypical PrPres gave rise to PrP^Sc and prion disease with a phenotype similar to those induced by rPrP fibrils. Significant differences in the sialylation pattern between atypical PrPres and PrP^Sc suggested that only a small sub-fraction of the PrP^C that is acceptable as a substrate for PrP^Sc could be also recruited by atypical PrPres. This can explain why atypical PrPres replicates slower than PrP^Sc and why PrP^Sc outcompetes atypical PrPres.

This study illustrates that transmissible prion diseases with very similar disease phenotypes could be produced via two alternative procedures: direct inoculation of recombinant PrP amyloid fibrils or in vitro-produced atypical PrPres. Moreover, this work showed that preparations of atypical PrPres free of PrP^Sc can give rise to transmissible diseases in wild type animals and that atypical PrPres generated in vitro is an adequate model for brain-derived atypical PrPres.