PLoS Pathogens | |
Unraveling the key to the resistance of canids to prion diseases | |
Martí Pumarola1  Hasier Eraña1  Natalia Fernández-Borges1  Enric Vidal2  Joaquín Castilla3  Tomás Mayoral4  Saioa R. Elezgarai5  Jorge de Castro6  Beatriz Parra7  Manuel A. Sánchez-Martín8  | |
[1] CIC bioGUNE, Parque tecnológico de Bizkaia, Derio, Bizkaia, Spain;Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain;Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain;Department of Animal Medicine and Surgery, Veterinary faculty, Universitat Autònoma de Barcelona (UAB), Bellaterra (Cerdanyola del Vallès), Barcelona, Spain;Department of Infectology, Scripps Florida, Jupiter, Florida, United States of America;IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain;Laboratorio Central de Veterinaria (LCV), Madrid, Spain;Servicio de Transgénesis, Nucleus, Universidad de Salamanca, Salamanca, Spain | |
关键词: Dogs; Animal prion diseases; Mouse models; Genetically modified animals; Pets; companion animals; Monoclonal antibodies; Protein structure; Sheep; | |
DOI : 10.1371/journal.ppat.1006716 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
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.
【 授权许可】
CC BY
【 预 览 】
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