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.
Highlights
Prion diseases or transmissible spongiform encephalopathies (TSEs), a group of fatal neurodegenerative disorders, have been described since the XVIIIth century when clinical signs of scrapie in sheep were reported in England [1]
Canids have long been considered resistant to prion infection given the absence of clinical disease despite exposure to the causal agent
Natural prion disorders include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, transmissible mink encephalopathy (TME) in mink, chronic wasting disease (CWD) in cervids, and Kuru, Creutzfeldt-Jakob disease (CJD), GerstmannStraussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and variably protease-sensitive prionopathy (VPSPr) in humans, which arise either sporadically–putatively spontaneous misfolding of PrPC–or are caused by mutations in the prion protein (PrP) encoding gene that are inherited as an autosomal dominant trait [4, 5]
Summary
Prion diseases or transmissible spongiform encephalopathies (TSEs), a group of fatal neurodegenerative disorders, have been described since the XVIIIth century when clinical signs of scrapie in sheep were reported in England [1]. As a consequence of the BSE epidemic which occurred in the United Kingdom during the 1990’s, several mammalian species became infected with BSE prions Such natural interspecies prion transmission, which had never been reported previously, gave rise to several new prion diseases including feline spongiform encephalopathy (FSE) in several feline species, TSE in a small number of non-human primates (NHP) and exotic ungulate spongiform encephalopathy (EUE) in several species of exotic ruminants of the Bovidae family kept in captivity [6, 7]. A wide variety of animal species are susceptible to prion disease including members of several mammalian families such as Bovidae, Cervidae, Muridae, Mustelidae, Felidae, Cricetidae, Caviidae, Leporidae, Suidae and Hominidae along with other primate families
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