Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection |
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Authors: | Tracy Haldiman Chae Kim Yvonne Cohen Wei Chen Janis Blevins Liuting Qing Mark L Cohen Jan Langeveld Glenn C Telling Qingzhong Kong Jiri G Safar |
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Institution: | From the Departments of ‡Pathology and ;**Neurology and ;§National Prion Disease Pathology Surveillance Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.;the ¶Central Veterinary Institute of Wageningen UR, 8200 AB Lelystad, The Netherlands, and ;the ‖Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523-1619 |
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Abstract: | The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrPSc particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrPSc is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers. |
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Keywords: | Molecular Evolution Neurobiology Neurodegeneration Prions Protein Conformation Sporadic Creutzfeldt-Jakob Disease |
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