A molecular switch controls interspecies prion disease transmission in mice

摘要

Transmissible spongiform encephalopathies are lethal neurodegenerative disorders that present with aggregated forms of the cellular prion protein (PrP~(C)), which are known as PrP~(Sc). Prions from different species vary considerably in their transmissibility to xenogeneic hosts. The variable transmission barriers depend on sequence differences between incoming PrP~(Sc) and host PrP~(C) and additionally, on strain-dependent conformational properties of PrP~(Sc). The β_(2)-α_(2) loop region within PrP~(C) varies substantially between species, with its structure being influenced by the residue types in the 2 amino acid sequence positions 170 (most commonly S or N) and 174 (N or T). In this study, we inoculated prions from 5 different species into transgenic mice expressing either disordered-loop or rigid-loop PrP~(C) variants. Similar β_(2)-α_(2) loop structures correlated with efficient transmission, whereas dissimilar loops correlated with strong transmission barriers. We then classified literature data on cross-species transmission according to the 170S/N polymorphism. Transmission barriers were generally low between species with the same amino acid residue in position 170 and high between those with different residues. These findings point to a triggering role of the local β_(2)-α_(2) loop structure for prion transmissibility between different species.