A Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesis
Prion 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 f...
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Veterinary Medicine
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ftunivcalgary:oai:prism.ucalgary.ca:1880/113749 2023-08-27T04:11:39+02:00 A Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesis Arifin, Maria Immaculata Gilch, Sabine Schätzl, Hermann Czub, Markus Jirik, Frank Mathiason, Candace Musiani, Marco 2021-08 application/pdf http://hdl.handle.net/1880/113749 https://doi.org/10.11575/PRISM/39109 eng eng Veterinary Medicine University of Calgary Arifin, M. I. (2021). A prion protein gene polymorphism at Codon 138 modulates Chronic Wasting Disease pathogenesis (Unpublished doctoral thesis). University of Calgary, Calgary, AB. http://dx.doi.org/10.11575/PRISM/39109 http://hdl.handle.net/1880/113749 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. prion chronic wasting disease caribou polymorphism pathogenesis Biology Biology--Cell Biology--Molecular Neuroscience Veterinary Science doctoral thesis 2021 ftunivcalgary https://doi.org/10.11575/PRISM/39109 2023-08-06T06:28:22Z Prion 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 ... Doctoral or Postdoctoral Thesis Rangifer tarandus PRISM - University of Calgary Digital Repository |
institution |
Open Polar |
collection |
PRISM - University of Calgary Digital Repository |
op_collection_id |
ftunivcalgary |
language |
English |
topic |
prion chronic wasting disease caribou polymorphism pathogenesis Biology Biology--Cell Biology--Molecular Neuroscience Veterinary Science |
spellingShingle |
prion chronic wasting disease caribou polymorphism pathogenesis Biology Biology--Cell Biology--Molecular Neuroscience Veterinary Science Arifin, Maria Immaculata A Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesis |
topic_facet |
prion chronic wasting disease caribou polymorphism pathogenesis Biology Biology--Cell Biology--Molecular Neuroscience Veterinary Science |
description |
Prion 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 ... |
author2 |
Gilch, Sabine Schätzl, Hermann Czub, Markus Jirik, Frank Mathiason, Candace Musiani, Marco |
format |
Doctoral or Postdoctoral Thesis |
author |
Arifin, Maria Immaculata |
author_facet |
Arifin, Maria Immaculata |
author_sort |
Arifin, Maria Immaculata |
title |
A Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesis |
title_short |
A Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesis |
title_full |
A Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesis |
title_fullStr |
A Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesis |
title_full_unstemmed |
A Prion Protein Gene Polymorphism at Codon 138 Modulates Chronic Wasting Disease Pathogenesis |
title_sort |
prion protein gene polymorphism at codon 138 modulates chronic wasting disease pathogenesis |
publisher |
Veterinary Medicine |
publishDate |
2021 |
url |
http://hdl.handle.net/1880/113749 https://doi.org/10.11575/PRISM/39109 |
genre |
Rangifer tarandus |
genre_facet |
Rangifer tarandus |
op_relation |
Arifin, M. I. (2021). A prion protein gene polymorphism at Codon 138 modulates Chronic Wasting Disease pathogenesis (Unpublished doctoral thesis). University of Calgary, Calgary, AB. http://dx.doi.org/10.11575/PRISM/39109 http://hdl.handle.net/1880/113749 |
op_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. |
op_doi |
https://doi.org/10.11575/PRISM/39109 |
_version_ |
1775354642589286400 |