Synthetic Prion Selection and Adaptation

Prion pathologies are characterized by the conformational conversion of the cellular prion protein (PrP C ) into a pathological infectious isoform, known as PrP Sc . The latter acquires different abnormal conformations, which are associated with specific pathological phenotypes. Recent evidence suggests that prions adapt their conformation to changes in the context of replication. This phenomenon is known as either prion selection or adaptation, where distinct conformations of PrP Sc with higher propensity to propagate in the new environment prevail over the others. Here, we show that a synthetically generated prion isolate, previously subjected to protein misfolding cyclic amplification (PMCA) and then injected in animals, is able to change its biochemical and biophysical properties according to the context of replication. In particular, in second transmission passage in vivo, two different prion isolates were found: one characterized by a predominance of the monoglycosylated band (PrP Sc -M) and the other characterized by a predominance of the diglycosylated one (PrP Sc -D). Neuropathological, biochemical, and biophysical assays confirmed that these PrP Sc possess distinctive characteristics. Finally, PMCA analysis of PrP Sc -M and PrP Sc -D generated PrP Sc (PrP Sc -PMCA) whose biophysical properties were different from those of both inocula, suggesting that PMCA selectively amplified a third PrP Sc isolate. Taken together, these results indicate that the context of replication plays a pivotal role in either prion selection or adaptation. By exploiting the ability of PMCA to mimic the process of prion replication in vitro, it might be possible to assess how changes in the replication environment influence the phenomenon of prion selection and adaptation.