TY - JOUR
T1 - Cofactors influence the biological properties of infectious recombinant prions.
AU - Fernández-Borges, Natalia
AU - Di Bari, Michele Angelo
AU - Eraña, Hasier
AU - Pirisinu, Laura
AU - Parra, Beatriz
AU - Elezgarai, Saioa R.
AU - Vanni, Ilaria
AU - López-Moreno, Raphael
AU - Vaccari, Gabriele
AU - Venegas, Vanessa
AU - Charco, Jorge M.
AU - Gil, David
AU - Harrathi, Chafik
AU - D'Agostino, Claudia
AU - Agrimi, Umberto
AU - Mayoral, Tomás
AU - Requena, Jesús R.
AU - Nonno, Romolo
AU - Castilla, Joaquín
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Prion diseases are caused by a misfolding of the cellular prion protein (PrP) to a pathogenic isoform named PrPSc. Prions exist as strains, which are characterized by specific pathological and biochemical properties likely encoded in the three-dimensional structure of PrPSc. However, whether cofactors determine these different PrPSc 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 PrPC to PrPSc. 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.
AB - Prion diseases are caused by a misfolding of the cellular prion protein (PrP) to a pathogenic isoform named PrPSc. Prions exist as strains, which are characterized by specific pathological and biochemical properties likely encoded in the three-dimensional structure of PrPSc. However, whether cofactors determine these different PrPSc 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 PrPC to PrPSc. 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.
KW - Cofactors
KW - In vitro propagation
KW - Infectious recombinant prions
KW - PMCA
KW - Prion strains
KW - TSE
U2 - 10.1007/s00401-017-1782-y
DO - 10.1007/s00401-017-1782-y
M3 - Article
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
ER -