Unraveling the key to the resistance of canids to prion diseases
One of the characteristics of prions is their ability to infect some species but not others and prion resistant species have been of special interest because of their potential in deciphering the determinants for susceptibility. Previously, we developed different in vitro and in vivo models to asses...
| Authors: | ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Publication date: | 2017 |
| Country: | España |
| Institution: | Universitat Autònoma de Barcelona |
| Repository: | Dipòsit Digital de Documents de la UAB |
| Language: | English |
| OAI Identifier: | oai:ddd.uab.cat:254029 |
| Online Access: | https://ddd.uab.cat/record/254029 https://dx.doi.org/urn:doi:10.1371/journal.ppat.1006716 |
| Access Level: | Open access |
| Keyword: | Malalties priòniques en els animals Gossos Prion diseases Prion |
| _version_ | 1878734954942169088 |
|---|---|
| author | Fernández-Borges, Natalia |
| author2 | Parra, Beatriz|||0000-0002-5371-7449 Vidal Barba, Enric|||0000-0002-4965-3286 Eraña, Hasier|||0000-0001-8776-4211 Sánchez-Martín, Manuel A.|||0000-0001-8370-1336 de Castro, Jorge|||0000-0002-2380-8956 Elezgarai, Saioa R.|||0000-0001-7054-9689 Pumarola i Batlle, Martí|||0000-0002-0935-7941 Mayoral, Tomás|||0000-0003-2644-1966 Castilla, Joaquín|||0000-0002-2216-1361 |
| author2_role | author author author author author author author author author |
| author_browse | Castilla, Joaquín|||0000-0002-2216-1361 Elezgarai, Saioa R.|||0000-0001-7054-9689 Eraña, Hasier|||0000-0001-8776-4211 Fernández-Borges, Natalia Mayoral, Tomás|||0000-0003-2644-1966 Parra, Beatriz|||0000-0002-5371-7449 Pumarola i Batlle, Martí|||0000-0002-0935-7941 Sánchez-Martín, Manuel A.|||0000-0001-8370-1336 Vidal Barba, Enric|||0000-0002-4965-3286 de Castro, Jorge|||0000-0002-2380-8956 |
| author_facet | Fernández-Borges, Natalia Parra, Beatriz|||0000-0002-5371-7449 Vidal Barba, Enric|||0000-0002-4965-3286 Eraña, Hasier|||0000-0001-8776-4211 Sánchez-Martín, Manuel A.|||0000-0001-8370-1336 de Castro, Jorge|||0000-0002-2380-8956 Elezgarai, Saioa R.|||0000-0001-7054-9689 Pumarola i Batlle, Martí|||0000-0002-0935-7941 Mayoral, Tomás|||0000-0003-2644-1966 Castilla, Joaquín|||0000-0002-2216-1361 |
| author_role | author |
| collection | Dipòsit Digital de Documents de la UAB |
| description | One of the characteristics of prions is their ability to infect some species but not others and prion resistant species have been of special interest because of their potential in deciphering the determinants for susceptibility. Previously, we developed different in vitro and in vivo models to assess the susceptibility of species that were erroneously considered resistant to prion infection, such as members of the Leporidae and Equidae families. Here we undertake in vitro and in vivo approaches to understand the unresolved low prion susceptibility of canids. Studies based on the amino acid sequence of the canine prion protein (PrP), together with a structural analysis in silico, identified unique key amino acids whose characteristics could orchestrate its high resistance to prion disease. Cell- and brain-based PMCA studies were performed highlighting the relevance of the D163 amino acid in proneness to protein misfolding. This was also investigated by the generation of a novel transgenic mouse model carrying this substitution and these mice showed complete resistance to disease despite intracerebral challenge with three different mouse prion strains (RML, 22L and 301C) known to cause disease in wild-type mice. These findings suggest that dog D163 amino acid is primarily, if not totally, responsible for the prion resistance of canids. Detection of individuals or whole species resistant to any infectious disease is vital to understand the determinants of susceptibility and to develop appropriate therapeutic and preventative strategies. Canids have long been considered resistant to prion infection given the absence of clinical disease despite exposure to the causal agent. Through extensive analysis of the canine prion protein we have detected a key amino acid that might be responsible for their universal resistance to prion disease. Using in vitro and in vivo models we demonstrated that the presence of this residue confers resistance to prion infection when introduced to susceptible animals, opening the way to develop a new therapeutic approach against these, at present, untreatable disorders. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_731bbaba8043e3ed7c4cd48e2c03c3ab |
| institution | Universitat Autònoma de Barcelona |
| instname_str | Universitat Autònoma de Barcelona |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:ddd.uab.cat:254029 |
| publishDate | 2017 |
| publishDateSort | 2017 |
| reponame_str | Dipòsit Digital de Documents de la UAB |
| spelling | Unraveling the key to the resistance of canids to prion diseases Fernández-Borges, Natalia Parra, Beatriz|||0000-0002-5371-7449 Vidal Barba, Enric|||0000-0002-4965-3286 Eraña, Hasier|||0000-0001-8776-4211 Sánchez-Martín, Manuel A.|||0000-0001-8370-1336 de Castro, Jorge|||0000-0002-2380-8956 Elezgarai, Saioa R.|||0000-0001-7054-9689 Pumarola i Batlle, Martí|||0000-0002-0935-7941 Mayoral, Tomás|||0000-0003-2644-1966 Castilla, Joaquín|||0000-0002-2216-1361 Malalties priòniques en els animals Gossos Prion diseases Prion One of the characteristics of prions is their ability to infect some species but not others and prion resistant species have been of special interest because of their potential in deciphering the determinants for susceptibility. Previously, we developed different in vitro and in vivo models to assess the susceptibility of species that were erroneously considered resistant to prion infection, such as members of the Leporidae and Equidae families. Here we undertake in vitro and in vivo approaches to understand the unresolved low prion susceptibility of canids. Studies based on the amino acid sequence of the canine prion protein (PrP), together with a structural analysis in silico, identified unique key amino acids whose characteristics could orchestrate its high resistance to prion disease. Cell- and brain-based PMCA studies were performed highlighting the relevance of the D163 amino acid in proneness to protein misfolding. This was also investigated by the generation of a novel transgenic mouse model carrying this substitution and these mice showed complete resistance to disease despite intracerebral challenge with three different mouse prion strains (RML, 22L and 301C) known to cause disease in wild-type mice. These findings suggest that dog D163 amino acid is primarily, if not totally, responsible for the prion resistance of canids. Detection of individuals or whole species resistant to any infectious disease is vital to understand the determinants of susceptibility and to develop appropriate therapeutic and preventative strategies. Canids have long been considered resistant to prion infection given the absence of clinical disease despite exposure to the causal agent. Through extensive analysis of the canine prion protein we have detected a key amino acid that might be responsible for their universal resistance to prion disease. Using in vitro and in vivo models we demonstrated that the presence of this residue confers resistance to prion infection when introduced to susceptible animals, opening the way to develop a new therapeutic approach against these, at present, untreatable disorders. https://ddd.uab.cat/record/254029 https://dx.doi.org/urn:doi:10.1371/journal.ppat.1006716 |
| spellingShingle | Unraveling the key to the resistance of canids to prion diseases Fernández-Borges, Natalia Malalties priòniques en els animals Gossos Prion diseases Prion |
| title | Unraveling the key to the resistance of canids to prion diseases |
| title_full | Unraveling the key to the resistance of canids to prion diseases |
| title_fullStr | Unraveling the key to the resistance of canids to prion diseases |
| title_full_unstemmed | Unraveling the key to the resistance of canids to prion diseases |
| title_short | Unraveling the key to the resistance of canids to prion diseases |
| title_sort | Unraveling the key to the resistance of canids to prion diseases |
| topic | Malalties priòniques en els animals Gossos Prion diseases Prion |
| topic_facet | Malalties priòniques en els animals Gossos Prion diseases Prion |
| url | https://ddd.uab.cat/record/254029 https://dx.doi.org/urn:doi:10.1371/journal.ppat.1006716 |