Unraveling the key to the resistance of canids to prion diseases
Fernández-Borges, Natalia (CIC bioGUNE. Parque tecnológico de Bizkaia)
Parra, Beatriz (Laboratorio Central de Veterinaria)
Vidal Barba, Enric (Institut de Recerca i Tecnologia Agroalimentàries. Centre de Recerca en Sanitat Animal)
Eraña, Hasier (CIC bioGUNE. Parque tecnológico de Bizkaia)
Sánchez-Martín, Manuel A. (Instituto de Investigación Biomédica de Salamanca)
de Castro, Jorge (Department of Infectology)
Elezgarai, Saioa R. (CIC bioGUNE. Parque tecnológico de Bizkaia)
Pumarola i Batlle, Martí (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animals)
Mayoral, Tomás (Laboratorio Central de Veterinaria)
Castilla, Joaquín (Basque Foundation for Science)

Date:	2017
Abstract:	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.
Grants:	Ministerio de Economía, Industria y Competitividad AGL2015-65046-C2-1-R Ministerio de Economía, Industria y Competitividad PCIN-2013-065
Note:	Altres ajuts: Eusko Jaurlaritza 2014111157
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Malalties priòniques en els animals ; Gossos ; Prion diseases ; Prion
Published in:	PLOS pathogens, Vol. 13 (november 2017) , ISSN 1553-7374

DOI: 10.1371/journal.ppat.1006716
PMID: 29131852

27 p, 13.9 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Centre de Recerca en Sanitat Animal (CReSA-IRTA)
Articles > Research articles
Articles > Published articles