Cofactors influence the biological properties of infectious recombinant prions
| Autor: | Beatriz Parra, Jorge M. Charco, Manuel Sánchez-Martín, Umberto Agrimi, Natalia Fernández-Borges, Claudia D'Agostino, Michele Angelo Di Bari, Tomás Mayoral, Gabriele Vaccari, Laura Pirisinu, Joaquín Castilla, Vanessa Venegas, Hasier Eraña, Chafik Harrathi, Jesús R. Requena, David Gil, Romolo Nonno, Saioa R. Elezgarai, Rafael López-Moreno, Ilaria Vanni |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Gene isoform Protein Folding animal diseases Mice Transgenic Cofactor Prion Proteins Pathology and Forensic Medicine law.invention Prion Diseases Pathogenesis 03 medical and health sciences Cellular and Molecular Neuroscience law Biological property Escherichia coli Animals Polymorphism Genetic biology Arvicolinae Brain In vitro Recombinant Proteins nervous system diseases 030104 developmental biology Biochemistry biology.protein Recombinant DNA Protein Misfolding Cyclic Amplification Protein folding Neurology (clinical) |
| Zdroj: | Acta neuropathologica. 135(2) |
| ISSN: | 1432-0533 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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