Classical BSE emergence from Nor98/atypical scrapie: Unraveling the shift vs. selection dichotomy in the prion field

Prion diseases can manifest with distinct phenotypes in a single species, a phenomenon known as prion strains. Upon cross-species transmission, alterations in the disease phenotype can occur, interpreted as the emergence of a new strain. Two main and non-mutually exclusive evolutionary hypotheses have been proposed to explain this phenomenon: the "conformational shift" or "deformed templating" and the "conformational selection." The conformational shift hypothesis proposes that the introduction of a new host prion protein (PrP^C) forces a change in the conformation of the pathological prion protein (PrP^Sc), causing the new prion strain emergence. On the contrary, the conformational selection model postulates that prion isolates are a conglomerate of PrP^Sc conformations with relative distribution frequencies, wherein the species barrier acts as a filter selecting the one fittest for the new species environment. Previous studies reported the emergence of the classical bovine spongiform encephalopathy agent (c-BSE) upon transmission of Nor98/atypical scrapie (AS) onto a bovine PrP. This study investigates the evolutionary dichotomy of this c-BSE emergence by using prion strain thermostability combined with protein misfolding cyclic amplification to distinguish between both strains. Our results suggest that the conformational shift could be the principal mechanism responsible for the c-BSE emergence. Furthermore, the selection model was dismissed as the key mechanism based on the analysis of an artificial c-BSE and AS mixture. The ability of the AS conformers to shift conformation to a c-BSE one supports the hypothesis that the epidemic c-BSE prion may have originated from the transmission of AS in cattle.