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Neurobiol Dis. 2016 Nov;95:204-9. doi: 10.1016/j.nbd.2016.07.025. Epub 2016 Jul 28.

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

Author information

1
McKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, FL 32611, USA.
2
McKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, FL 32611, USA; Department of Neuroscience, Genetics Institute and Center for Translational Research on Neurodegenerative Disorders, University of Florida, Gainesville, FL 32611, USA.
3
McKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, FL 32611, USA; Department of Neuroscience, Genetics Institute and Center for Translational Research on Neurodegenerative Disorders, University of Florida, Gainesville, FL 32611, USA. Electronic address: pedro.ffunez@gmail.com.

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.

KEYWORDS:

Dog; Drosophila; Misfolding; Mouse; Neurotoxicity; Prion protein; Protective substitution; Sequence alignment

PMID:
27477054
PMCID:
PMC5010947
DOI:
10.1016/j.nbd.2016.07.025
[Indexed for MEDLINE]
Free PMC Article

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