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

J. Sanchez-Garcia, K. Jensen, Y. Zhang, D. E. Rincon-Limas, P. Fernandez-Funez

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)204-209
Number of pages6
JournalNeurobiology of Disease
Volume95
DOIs
StatePublished - Nov 1 2016

Bibliographical note

Funding Information:
We thank S. Supatappone and the Bloomington Drosophila Stock Center (NIH P40OD018537) for transgenic flies and J. Castilla for the MoPrP-N159D construct. This work was supported by the National Institutes of Health grant DP2 OD002721-01 to PF-F. JS-G was supported by a postdoctoral fellowship from the Basque Government .

Publisher Copyright:
© 2016 Elsevier Inc.

Keywords

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

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