A single amino acid (Asp159) from the dog prion protein suppresses the toxicity of the mouse prion protein in Drosophila

Sanchez-Garcia, Jonatan; Jensen, Kurt; Zhang, Y.; Rincón-Limas, Diego E.; Fernández-Fúnez, Pedro

doi:10.1016/j.nbd.2016.07.025

Cited by 18 publications

(31 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Assuming these residues participate in the PrP conversion to the disease associated isoform, D158 probably disturbs that PrP region as well as establishing a salt bridge with R135 limiting the latter’s role in conversion. This is supported by recent findings in transgenic Drosophila expressing mouse PrP with N158D substitution where it impairs the locomotor dysfunction developed when wild-type mouse PrP is expressed [ 61 ].…”

Section: Discussionsupporting

confidence: 60%

Unraveling the key to the resistance of canids to prion diseases

Fernández‐Borges

Parra²,

Vidal

et al. 2017

PLoS Pathog

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 60%

Unraveling the key to the resistance of canids to prion diseases

Fernández‐Borges

Parra²,

Vidal

et al. 2017

PLoS Pathog

View full text Add to dashboard Cite

show abstract

“…Considerable amounts of data have been generated suggesting that canine PrP C is highly resistant to conformation change to PrP res compared to prion susceptible species. 22,32,36,37,41,42 Our group has now established, both in vivo and in vitro, that the amino acid residue in position 163 is the key determinant 32,33 and that an aspartic or a glutamic acid in this position (or equivalent in other species) is what conferred resistance to prion infection in the models in which those proteins were expressed. 32,34 Furthermore, these PrP C that are highly resistant to conformation change showed a dominant negative effect when co-expressed with WT mouse PrP.…”

Section: Discussionmentioning

confidence: 99%

Dogs are resistant to prion infection, due to the presence of aspartic or glutamic acid at position 163 of their prion protein

et al. 2020

View full text Add to dashboard Cite

Unlike other species, prion disease has never been described in dogs even though they were similarly exposed to the bovine spongiform encephalopathy (BSE) agent. This resistance prompted a thorough analysis of the canine PRNP gene and the presence of a negatively charged amino acid residue in position 163 was readily identified as potentially fundamental as it differed from all known susceptible species. In the present study, the first transgenic mouse model expressing dog prion protein (PrP) was generated and challenged intracerebrally with a panel of prion isolates, none of which could infect them. The brains of these mice were subjected to in vitro prion amplification and failed to find even minimal amounts of misfolded prions providing definitive experimental evidence that dogs are resistant to prion disease. Subsequently, a second transgenic model was generated in which aspartic acid in position 163 was substituted for asparagine (the most common in prion susceptible species) resulting in susceptibility to BSE‐derived isolates. These findings strongly support the hypothesis that the amino acid residue at position 163 of canine cellular prion protein (PrPC) is a major determinant of the exceptional resistance of the canidae family to prion infection and establish this as a promising therapeutic target for prion diseases.

show abstract

“…Utilizing the versatile fruit fly, we generated transgenic flies expressing mouse PrP with the N159D substitution ( Sanchez-Garcia et al, 2016 ). Expression of mouse PrP-N159D showed improved locomotor performance compared to flies expressing mouse PrP-WT, a change that correlated with lower levels of pathogenic conformations of PrP ( Sanchez-Garcia et al, 2016 ). We recently conducted the reverse experiment by introducing the D159N substitution in dog PrP in flies.…”

Section: Dog Prp – D159mentioning

confidence: 99%

Insight From Animals Resistant to Prion Diseases: Deciphering the Genotype – Morphotype – Phenotype Code for the Prion Protein

Myers

Cembran

Fernández-Fúnez

2020

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Prion diseases are a group of neurodegenerative diseases endemic in humans and several ruminants caused by the misfolding of native prion protein (PrP) into pathological conformations. Experimental work and the mad-cow epidemic of the 1980s exposed a wide spectrum of animal susceptibility to prion diseases, including a few highly resistant animals: horses, rabbits, pigs, and dogs/canids. The variable susceptibility to disease offers a unique opportunity to uncover the mechanisms governing PrP misfolding, neurotoxicity, and transmission. Previous work indicates that PrP-intrinsic differences (sequence) are the main contributors to disease susceptibility. Several residues have been cited as critical for encoding PrP conformational stability in prion-resistant animals, including D/E159 in dog, S167 in horse, and S174 in rabbit and pig PrP (all according to human numbering). These amino acids alter PrP properties in a variety of assays, but we still do not clearly understand the structural correlates of PrP toxicity. Additional insight can be extracted from comparative structural studies, followed by molecular dynamics simulations of selected mutations, and testing in manipulable animal models. Our working hypothesis is that protective amino acids generate more compact and stable structures in a C-terminal subdomain of the PrP globular domain. We will explore this idea in this review and identify subdomains within the globular domain that may hold the key to unravel how conformational stability and disease susceptibility are encoded in PrP.

show abstract

A single amino acid (Asp159) from the dog prion protein suppresses the toxicity of the mouse prion protein in Drosophila

Cited by 18 publications

References 30 publications

Unraveling the key to the resistance of canids to prion diseases

Unraveling the key to the resistance of canids to prion diseases

Dogs are resistant to prion infection, due to the presence of aspartic or glutamic acid at position 163 of their prion protein

Insight From Animals Resistant to Prion Diseases: Deciphering the Genotype – Morphotype – Phenotype Code for the Prion Protein

Contact Info

Product

Resources

About