Investigating strain diversity of Creutzfeldt-Jakob disease in Canada
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Date
2024-01-19
Authors
Myskiw, Jennifer
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Abstract
Prions are infectious proteins that cause rare but invariably fatal neurodegenerative diseases in humans and other mammals. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of human prion disease, with an annual prevalence of 1-2 cases per million individuals. Though extremely rare, sCJD is devastating. This disease is rapid, with most patients dying within 5 months from the onset of symptoms and no available treatments. sCJD is heterogeneous, with diverse clinical signs, brain lesion profiles, and disease durations. It is believed this variability is attributed to different prion strains, which are influenced by host genetics and the shape of the misfolded protein. Strain diversity is poorly understood and remains to be explored experimentally. For these reasons, we have developed methodologies to exploit strain-specific properties and applied them in a retrospective analysis of 31 sCJD cases in Canada. We characterized the biochemical properties of the pathogenic prion proteins from these cases using thermal denaturation assays, capillary-electrophoresis immunoassays, and protein seeding kinetic assays. Atypical cases were inoculated into a novel animal model to analyze strain-specific properties such as incubation periods, clinical signs, and brain lesions. Within our cohort of 31 sCJD patients, we identified two atypical sCJD cases and two cases of a rare strain of sCJD called variably-protease sensitive prionopathy. We propose the two atypical sCJD cases represent novel strains of sCJD in Canada. Additionally, we have developed a sCJD strain baseline through which atypical cases could readily be identified in the future. Understanding prion strains has implications for the detection of zoonotic transmission as well as for the development of therapeutics.
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Keywords
Creutzfeldt-Jakob Disease, Prion Diseases, Neurodegenerative Diseases