The Role of Quaternary Structure Organization in Prion Strain Selection and Adaptation
Date
2023-08
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Abstract
Prion diseases are fatal and infectious neurodegenerative diseases caused by the misfolded, protease-resistant, and aggregated prion protein isoform, PrPSc. Unlike conventional pathogens, the propagation of prions does not depend on the replication of genetic material, but different cases of infection can lead to PrPSc adopting specific conformations resulting in different and stably transmissible phenotypic properties that are, by definition, the determinants of different strains. The distribution of PrPSc quaternary structure has previously been determined to vary across prion strains, and different PrPSc aggregate assemblies in turn harbour varying levels of infectivity. We were interested in determining how PrPSc aggregate size modulate strain properties and how these properties are affected by different inoculation routes, specifically in comparing peripheral versus intracerebral infection. Using in vivo murine models, we explored prion disease pathogenesis and strain selection upon inoculation of different PrPSc protein quaternary structures or prion strains. Transgenic mice overexpressing cervid prion protein inoculated with different elk chronic wasting disease PrPSc fractions exhibited strikingly different survival times and disease phenotypes, including variations in the prion biochemical, neuropathological, and biophysical profiles; interestingly, these properties converged upon passaging, though not the differing clinical signs. Gene-targeted mice expressing the cervid prion protein at physiological levels infected with CWD prions either directly into the brain or from the periphery resulted in different biochemical and neuropathological properties, notably with a converging conformational profile among the peripherally inoculated group. Similar observations were recorded where animals peripherally inoculated with CWD prion aggregates exhibited markedly reduced variations in survival times compared to infection directly into the brain. These results indicate that the direct selection of PrPSc conformers, or PrPSc conformational mutation, is likely to occur in the presence of a barrier interfering with the ideal replication setting as adaptation under a more restrictive set of circumstances takes place. This research demonstrates the intricacies of prion strain selection and adaptation that would provide novel insight into future investigations of the evolution and emergence of prion strains.
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Keywords
prion, transmissible spongiform encephalopathy, protein quaternary structure, chronic wasting disease, CWD
Citation
Chang, S. C. (2023). The role of quaternary structure organization in prion strain selection and adaptation (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.