Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection

• Published in: The Journal of biological chemistry Vol. 288; no. 41; pp. 29846 - 29861
• Main Authors: Haldiman, Tracy, Kim, Chae, Cohen, Yvonne, Chen, Wei, Blevins, Janis, Qing, Liuting, Cohen, Mark L., Langeveld, Jan, Telling, Glenn C., Kong, Qingzhong, Safar, Jiri G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.10.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptation, Physiological - genetics; Animals; Blotting, Western; Brain - metabolism; Brain - pathology; chronic wasting disease; classification; Creutzfeldt-Jakob Syndrome - genetics; Creutzfeldt-Jakob Syndrome - metabolism; creutzfeldt-jakob-disease; dependent immunoassay; Evolution, Molecular; Humans; Immunoassay; Membrane Biology; Molecular Evolution; molecular-basis; Mutation; Neurobiology; Neurodegeneration; Prions; Prions - chemistry; Prions - genetics; Prions - metabolism; protein; Protein Conformation; Protein Stability; PrPSc Proteins - chemistry; PrPSc Proteins - genetics; PrPSc Proteins - metabolism; scrapie; Selection, Genetic; Sporadic Creutzfeldt-Jakob Disease; strain variation; transgenic mice; transmissible mink encephalopathy; Protein Conformation; Sporadic Creutzfeldt-Jakob Disease; Neurodegeneration; Prions; Molecular Evolution; Neurobiology
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M113.500108

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. Background: Mechanism of prion adaptation and evolution has not been fully elucidated. Results: Distinct human prion particles co-exist and undergo competitive selection during replication. Conclusion: The process is governed by preferential replication of the least stable pathogenic conformers. Significance: The spectrum of conformers in wild human prion isolates enables adaptation and evolution by selection of the progressively less stable and faster replicating subset.