The Role of Quaternary Structure Organization in Prion Strain Selection and Adaptation

Chang, Sheng Chun

The Role of Quaternary Structure Organization in Prion Strain Selection and Adaptation

dc.contributor.advisor	Gilch, Sabine
dc.contributor.author	Chang, Sheng Chun
dc.contributor.committeemember	Braun, Janice
dc.contributor.committeemember	Gilleard, John
dc.contributor.committeemember	Tsutsui, Shigeki
dc.contributor.committeemember	Booth, Stephanie
dc.date	2023-11
dc.date.accessioned	2023-08-14T21:34:47Z
dc.date.available	2023-08-14T21:34:47Z
dc.date.issued	2023-08
dc.description.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.
dc.identifier.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.
dc.identifier.uri	https://hdl.handle.net/1880/116858
dc.identifier.uri	https://dx.doi.org/10.11575/PRISM/41700
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	prion
dc.subject	transmissible spongiform encephalopathy
dc.subject	protein quaternary structure
dc.subject	chronic wasting disease
dc.subject	CWD
dc.subject.classification	Biology--Molecular
dc.subject.classification	Veterinary Science
dc.subject.classification	Microbiology
dc.subject.classification	Neuroscience
dc.title	The Role of Quaternary Structure Organization in Prion Strain Selection and Adaptation
dc.type	doctoral thesis
thesis.degree.discipline	Medicine – Biochemistry and Molecular Biology
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.