title: New Molecular Insight into Mechanism of Evolution of Mammalian Synthetic Prions.
abstract: Previous studies established that transmissible prion diseases could be induced by in vitro-produced recombinant prion protein (PrP) fibrils with structures that are fundamentally different from that of authentic PrP scrapie isoform (PrP(Sc)). To explain evolution of synthetic prions, a new mechanism referred to as deformed templating was introduced. Here, we asked whether an increase in expression level of the cellular form of PrP (PrP(C)) speeds up the evolution of synthetic strains in vivo. We found that in transgenic mice that overexpress hamster PrP(C), PrP(C) overexpression accelerated recombinant PrP fibril-induced conversion of PrP(C) to the abnormal proteinase K-resistant state, referred to as atypical PrPres, which was the first product of PrP(C) misfolding in vivo. However, overexpression of PrP(C) did not facilitate the second step of synthetic strain evolution-transition from atypical PrPres to PrP(Sc), which is attributed to the stochastic nature of rare deformed templating events. In addition, the potential of atypical PrPres to interfere with replication of a short-incubation time prion strain was investigated. Atypical PrPres was found to interfere strongly with replication of 263K in vitro; however, it did not delay prion disease in animals. The rate of deformed templating does not depend on the concentration of substrate and is hence more likely to be controlled by the intrinsic rate of conformational errors in templating alternative self-propagating states.
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Natallia
authors.initials: N
authors.lastname: Makarava
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Regina
authors.initials: R
authors.lastname: Savtchenko
authors.affiliation: Medical Research Service, Veterans Affairs Medical Center, University of Maryland, Baltimore, Maryland.
authors.forename: Irina
authors.initials: I
authors.lastname: Alexeeva
authors.affiliation: Medical Research Service, Veterans Affairs Medical Center, University of Maryland, Baltimore, Maryland; Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Rohwer
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: baskakov@umaryland.edu.
authors.forename: Ilia V
authors.initials: IV
authors.lastname: Baskakov
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D006224:Cricetinae; D019286:Endopeptidase K / Q000378:metabolism; D008322:Mammals / Q000378:metabolism*; D051379:Mice; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*
chemical_list: D018620:PrPSc Proteins; D011328:Prions; D019286:Endopeptidase K