Met166 -Glu168 residues in human PrP β2-α2 loop account for evolutionary resistance to prion infection.

Abstract

AimsThe amino acid sequence of prion protein (PrP) is a key determinant in the transmissibility of prion diseases. While PrP sequence is highly conserved among mammalian species, minor changes in the PrP amino acid sequence may confer alterations in the transmissibility of prion diseases. Classical bovine spongiform encephalopathy (C‐BSE) is the only zoonotic prion strain reported to date causing variant Creutzfeldt‐Jacob disease (vCJD) in humans, although experimental transmission points to atypical L‐BSE and some classical scrapie isolates as also zoonotic. The precise molecular elements in the human PrP sequence that limit the transmissibility of prion strains such as sheep/goat scrapie or cervid chronic wasting disease (CWD) are not well known.MethodsThe transmissibility of a panel of diverse prions from different species was compared in transgenic mice expressing either wild‐type human PrPC (MDE‐HuTg340) or a mutated human PrPC harbouring Val166‐Gln168 amino acid changes (VDQ‐HuTg372) in the β2‐α2 loop instead of Met166‐Glu168 wild‐type variants.ResultsVDQ‐HuTg372 mice were more susceptible to prions than MDE‐HuTg340 mice in a strain‐dependent manner.ConclusionsMet166‐Glu168 amino acid residues present in wild‐type human PrPC are molecular determinants that limit the propagation of most prion strains assayed in the human PrP context.