A Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesis

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dc.contributor.advisorGilch, Sabine
dc.contributor.authorArifin, Maria Immaculata
dc.contributor.committeememberSchätzl, Hermann
dc.contributor.committeememberCzub, Markus
dc.contributor.committeememberJirik, Frank
dc.contributor.committeememberMathiason, Candace
dc.contributor.committeememberMusiani, Marco
dc.date2021-11
dc.date.accessioned2021-08-18T21:12:22Z
dc.date.available2021-08-18T21:12:22Z
dc.date.issued2021-08
dc.description.abstractPrion diseases are fatal and infectious neurodegenerative diseases caused by prions. Chronic wasting disease (CWD) is a prion disease of cervids found in North America (NA), Scandinavia and South Korea. Although there are no reports of CWD in caribou (Rangifer tarandus spp.) in NA so far, previous findings show that reindeer (R. t. tarandus) are susceptible to CWD. Single amino acid substitutions (SAAS) within the cervid prion protein (PrP) sequence have been shown to prolong survival times and produce incomplete attack rates upon CWD infection. Prion protein SAAS have been found in caribou populations in NA, including a serine to asparagine substitution at codon 138 (S138N). Previous studies reported that animals harboring the N variant at this codon were either resistant or less susceptible to natural CWD prion exposure. Based on these reports, we hypothesized that the S138N PrP amino acid substitution modulates CWD pathogenesis. We report that the 138N allele frequency is rare among caribou in areas with high risk of contact with CWD-infected species, particularly in woodland caribou (R. t. caribou) herds in Saskatchewan and Alberta. We also report that the barren-ground caribou (R. t. groenlandicus) herds have higher frequencies of the 138N allele. We found that the S138N SAAS did not alter endogenous PrP properties, but rather impairs the prion conversion process. Transgenic knock-in (KI) mice expressing the 138NN PrP genotype did not develop clinical disease up to 700 days post-inoculation (dpi), whilst their wild-type deer (138SS) counter parts succumbed to CWD between ~450-580 dpi. The 138NN KI mice did, however, harbor prions capable of inducing conversion in an in vitro prion conversion assay. Remarkably, even upon intracerebral prion inoculation, seeding activity was first detected in the spleens of these KI mice. Our findings provide new insights into the role of PrP genotype in tissue tropism of prion replication. Caribou in NA are a Threatened species and an essential resource for Indigenous people. Thus, determining the mechanisms by which the 138N allele modulates CWD pathogenesis is important for future CWD management strategies, especially in areas where caribou are at a high risk of contracting the disease.en_US
dc.identifier.citationArifin, M. I. (2021). A prion protein gene polymorphism at Codon 138 modulates Chronic Wasting Disease pathogenesis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/39109
dc.identifier.urihttp://hdl.handle.net/1880/113749
dc.language.isoengen_US
dc.publisher.facultyVeterinary Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity 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.en_US
dc.subjectprionen_US
dc.subjectchronic wasting diseaseen_US
dc.subjectcaribouen_US
dc.subjectpolymorphismen_US
dc.subjectpathogenesisen_US
dc.subject.classificationBiologyen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationBiology--Molecularen_US
dc.subject.classificationNeuroscienceen_US
dc.subject.classificationVeterinary Scienceen_US
dc.titleA Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesisen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineVeterinary Medical Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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