Conformational transformation and selection of synthetic prion strains |
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Authors: | Ghaemmaghami Sina Watts Joel C Nguyen Hoang-Oanh Hayashi Shigenari DeArmond Stephen J Prusiner Stanley B |
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Institution: | 1 Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA 94143, USA2 Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA3 Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA |
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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. |
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Keywords: | MoSP mouse synthetic prion CJD Creutzfeldt-Jakob disease PrP prion protein PrPC cellular PrP TME transmissible mink encephalopathy Tg transgenic wt wild type recMoPrP recombinant mouse PrP PBS phosphate-buffered saline PK proteinase K RML Rocky Mountain Laboratory DMEM Dulbecco's modified Eagle's medium MEM minimum essential medium PAMAM polyamidoamine H& E hematoxylin-eosin PBST PBS plus 0 1% Tween 20 |
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