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

Abstract Misfolding of the prion protein (PrP) is the key step in the transmission of spongiform pathologies in humans and several animals. Although PrP is highly conserved in mammals, a few changes in the sequence of endogenous PrP are proposed to confer protection to dogs, which were highly expose...

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Published in:Neurobiology of disease 2016-11, Vol.95, p.204-209
Main Authors: Sanchez-Garcia, J, Jensen, K, Zhang, Y, Rincon-Limas, D.E, Fernandez-Funez, P
Format: Article
Language:English
Subjects:
Amino Acid Sequence - physiology
Animals
Animals, Genetically Modified
Aspartic Acid - genetics
Aspartic Acid - metabolism
Dog
Dogs
Drosophila
Drosophila melanogaster
Mice
Misfolding
Mouse
Neurology
Neurotoxicity
Prion protein
Prions - genetics
Prions - metabolism
Protective substitution
Sequence alignment
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Summary:Abstract Misfolding of the prion protein (PrP) is the key step in the transmission of spongiform pathologies in humans and several animals. Although PrP is highly conserved in mammals, a few changes in the sequence of endogenous PrP are proposed to confer protection to dogs, which were highly exposed to prion during the mad-cow epidemics. D159 is a unique amino acid found in PrP from dogs and other canines that was shown to alter surface charge, but its functional relevance has never been tested in vivo . Here, we show in transgenic Drosophila that introducing the N159D substitution on mouse PrP decreases its turnover. Additionally, mouse PrP-N159D demonstrates no toxicity and accumulates no pathogenic conformations, suggesting that a single D159 substitution is sufficient to prevent PrP conformational change and pathogenesis. Understanding the mechanisms mediating the protective activity of D159 is likely to lessen the burden of prion diseases in humans and domestic animals.
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2016.07.025