title: Conformational transformation and selection of synthetic prion strains.
abstract: Prion protein is capable of folding into multiple self-replicating prion strains that produce phenotypically distinct neurological disorders. Although prion strains often breed true upon passage, they can also transform or "mutate" despite being devoid of nucleic acids. To dissect the mechanism of prion strain transformation, we studied the physicochemical evolution of a mouse synthetic prion (MoSP) strain, MoSP1, after repeated passage in mice and cultured cells. We show that MoSP1 gradually adopted shorter incubation times and lower conformational stabilities. These changes were accompanied by structural transformation, as indicated by a shift in the molecular mass of the protease-resistant core of MoSP1 from approximately 19 kDa [MoSP1(2)] to 21 kDa [MoSP1(1)]. We show that MoSP1(1) and MoSP1(2) can breed with fidelity when cloned in cells; however, when present as a mixture, MoSP1(1) preferentially proliferated, leading to the disappearance of MoSP1(2). In culture, the rate of this transformation process can be influenced by the composition of the culture media and the presence of polyamidoamines. Our findings demonstrate that prions can exist as a conformationally diverse population of strains, each capable of replicating with high fidelity. Rare conformational conversion, followed by competitive selection among the resulting pool of conformers, provides a mechanism for the adaptation of the prion population to its host environment.
authors.affiliation: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Ghaemmaghami
authors.forename: Joel C
authors.initials: JC
authors.lastname: Watts
authors.forename: Hoang-Oanh
authors.initials: HO
authors.lastname: Nguyen
authors.forename: Shigenari
authors.initials: S
authors.lastname: Hayashi
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000682:Amyloid; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D010450:Endopeptidases / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000145:classification* / Q000235:genetics; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D011328:Prions / Q000737:chemistry* / Q000502:physiology*; D011487:Protein Conformation; D012641:Selection, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D000682:Amyloid; D011328:Prions; D010450:Endopeptidases