Journal Article

Cofactors influence the biological properties of infectious recombinant prions

D’Agostino, Claudia, Castilla, Joaquín, Mayoral, Tomás, Di Bari, Michele A., Charco, Jorge M., Requena, Jesús R., Venegas, Vanessa, Nonno, Romolo, Parra, Beatriz, Elezgarai, Saioa R., López-Moreno, Rafael, Vaccari, Gabriele, Agrimi, Umberto, Harrathi, Chafik, Pirisinu, Laura, Vanni, Ilaria, Fernández-Borges, Natalia, Eraña, Hasier, Gil, David, Sánchez-Martín, Manuel

2018

Overview

Prion diseases are caused by a misfolding of the cellular prion protein (PrP) to a pathogenic isoform named PrP Sc . Prions exist as strains, which are characterized by specific pathological and biochemical properties likely encoded in the three-dimensional structure of PrP Sc . However, whether cofactors determine these different PrP Sc conformations and how this relates to their specific biological properties is largely unknown. To understand how different cofactors modulate prion strain generation and selection, Protein Misfolding Cyclic Amplification was used to create a diversity of infectious recombinant prion strains by propagation in the presence of brain homogenate. Brain homogenate is known to contain these mentioned cofactors, whose identity is only partially known, and which facilitate conversion of PrP C to PrP Sc . We thus obtained a mix of distinguishable infectious prion strains. Subsequently, we replaced brain homogenate, by different polyanionic cofactors that were able to drive the evolution of mixed prion populations toward specific strains. Thus, our results show that a variety of infectious recombinant prions can be generated in vitro and that their specific type of conformation, i.e., the strain, is dependent on the cofactors available during the propagation process. These observations have significant implications for understanding the pathogenesis of prion diseases and their ability to replicate in different tissues and hosts. Importantly, these considerations might apply to other neurodegenerative diseases for which different conformations of misfolded proteins have been described.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V
• Subject: Analysis / Animals / Arvicolinae / Brain - metabolism / Brain - pathology / Cofactors / Escherichia coli / Medicine / Medicine & Public Health / Mice, Transgenic / Nervous system diseases / Neurodegenerative diseases / Neurosciences / Original Paper / Pathology / Polymorphism, Genetic / Prion Diseases - metabolism / Prion protein / Prion Proteins - genetics / Prion Proteins - metabolism / Prions / Prions (Proteins) / Protein Folding / Recombinant Proteins - metabolism