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Acta Neuropathol. 2018 Feb;135(2):179-199. doi: 10.1007/s00401-017-1782-y. Epub 2017 Nov 1.

Cofactors influence the biological properties of infectious recombinant prions.

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CIC bioGUNE, Parque tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain.
Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy.
Servicio de Transgénesis, Nucleus, Universidad de Salamanca, Salamanca, Spain.
IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain.
Laboratorio Central de Veterinaria (LCV), Madrid, Spain.
CIMUS Biomedical Research Institute & Department of Medical Sciences, University of Santiago de Compostela-IDIS, Santiago de Compostela, Spain.
CIC bioGUNE, Parque tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain.
IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain.


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.


Cofactors; In vitro propagation; Infectious recombinant prions; PMCA; Prion strains; TSE

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