The extent of protease resistance of misfolded prion protein is highly dependent on the salt concentration.

Transmissible spongiform encephalopathies are neurodegenerative diseases caused by prions in mammals. An aberrantly folded protein (PrP(Sc)) is the main component of these proteinaceous infectious particles. Prions exhibit strong resistance to protease digestion, which is typically exploited for biochemical discrimination from its native cellular form (PrP(C)). This classical feature has been partially challenged by the isolation of sizeable amounts of protease-sensitive PrP(Sc) isoforms that self-propagate in vivo. Here, we report that the degree of PrP(Sc) protease resistance is highly dependent on the concentration of salt in the solution. Similar changes were observed in PrP(Sc) obtained from different strains and species. Strikingly, the effect of salt is reversible and is associated with changes on the size of PrP(Sc) particles, but surprisingly, the more protease-sensitive species consists of a larger size. These findings shed light on the mechanistic aspects of prion proteolysis and should be considered when assessing samples of biomedical relevance.