Prion diseases are a group of transmissible fatal neurodegenerative disorders associated with the aggregation of monomeric prion protein into fibrillar amyloid-like deposits. Strain diversity and transmission barriers are two key features of mammalian prion propagation, and are believed to be related to the three-dimensional structures of the prion fibrils. The ability of prion protein to form structurally distinct aggregates, i.e., strains, which can lead to different disease phenotypes is an interesting yet puzzling aspects of prions. The characteristics of prion strains are crucial for the interspecies transmission which is much less efficient compared to the transmission within the same species. Lack of conformational and sequence overlap can give rise to barriers in prion transmission between different species. The Y145Stop prion protein (PrP23-144) variant, which has been linked to a heritable prionopathy in humans, is a useful in vitro model for investigating the phenomena of prion strains and transmissibility barriers. Low resolution studies have shown that the seeding specificities of mammalian PrP23-144 variants are correlated with the fibril conformation and recently we have used solid-state NMR to establish that human, mouse and Syrian hamster PrP23-144 variants adopt distinct amyloid core structures. Here, we use solid-state NMR to gain atomic level insights into cross-seeding reactions between the PrP23-144 variants where the amyloid formation by a monomeric protein from one species is seeded with preformed fibril seeds from another species. Remarkably, we find that the conformational switching can be observed in some cases. Depending on the experimental conditions the newly formed PrP23-144 amyloids can adopt a structure different from the native one of both species, that resembles the one obtained in an unseeded reaction of the native parent protein or that of the conformation of the seed from a different species.

Cross-seeding specificities of mammalian Y145Stop prion protein amyloids probed by solid-state NMR

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.