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PLoS Pathog. 2019 Mar 25;15(3):e1007662. doi: 10.1371/journal.ppat.1007662. eCollection 2019 Mar.

Full restoration of specific infectivity and strain properties from pure mammalian prion protein.

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Departments of Biochemistry and Cell Biology at Darthmouth, Hanover, New Hampshire, United States of America.
Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy.
Tanz Centre for Research in Neurodegenerative Diseases and Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.


The protein-only hypothesis predicts that infectious mammalian prions are composed solely of PrPSc, a misfolded conformer of the normal prion protein, PrPC. However, protein-only PrPSc preparations lack significant levels of prion infectivity, leading to the alternative hypothesis that cofactor molecules are required to form infectious prions. Here, we show that prions with parental strain properties and full specific infectivity can be restored from protein-only PrPSc in vitro. The restoration reaction is rapid, potent, and requires bank vole PrPC substrate, post-translational modifications, and cofactor molecules. To our knowledge, this represents the first report in which the essential properties of an infectious mammalian prion have been restored from pure PrP without adaptation. These findings provide evidence for a unified hypothesis of prion infectivity in which the global structure of protein-only PrPSc accurately stores latent infectious and strain information, but cofactor molecules control a reversible switch that unmasks biological infectivity.

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