Molecular Neurobiology

, Volume 55, Issue 7, pp 6182–6192 | Cite as

An Amino Acid Substitution Found in Animals with Low Susceptibility to Prion Diseases Confers a Protective Dominant-Negative Effect in Prion-Infected Transgenic Mice

  • Alicia Otero
  • Rosa Bolea
  • Carlos Hedman
  • Natalia Fernández-Borges
  • Belén Marín
  • Óscar López-Pérez
  • Tomás Barrio
  • Hasier Eraña
  • Manuel A. Sánchez-Martín
  • Marta Monzón
  • Juan José Badiola
  • Joaquín Castilla


While prion diseases have been described in numerous species, some, including those of the Canidae family, appear to show resistance or reduced susceptibility. A better understanding of the factors underlying prion susceptibility is crucial for the development of effective treatment and control measures. We recently demonstrated resistance to prion infection in mice overexpressing a mutated prion protein (PrP) carrying a specific amino acid substitution characteristic of canids. Here, we show that coexpression of this mutated PrP and wild-type mouse PrP in transgenic mice inoculated with different mouse-adapted prion strains (22 L, ME7, RML, and 301C) significantly increases survival times (by 45 to 113%). These data indicate that this amino acid substitution confers a dominant-negative effect on PrP, attenuating the conversion of PrPC to PrPSc and delaying disease onset without altering the neuropathological properties of the prion strains. Taken together, these findings have important implications for the development of new treatment approaches for prion diseases based on dominant-negative proteins.


TSE Prion infection Transgenic mouse models Transmissible spongiform encephalopathies Prion propagation Canine PrP 



We thank MINECO for the Severo Ochoa Excellence Accreditation (SEV-2016-0644). The authors would like to thank the following for their support: the IKERBasque Foundation, the staff at the CIC bioGUNE animal facility, Dr. Belén Pintado for the Tga20 mouse embryo rederivation, Dr. Glenn Telling for kindly providing the 5C6 antibody, and Patricia Piñeiro, Silvia Ruiz, and Sonia Gómez for their technical assistance. The authors would also like to acknowledge Sara Gutiérrez for the image editing. Alicia Otero was supported by a research grant from the Government of Aragón (C020/2014) cofinanced by the European Social Fund.

Funding Information

This work was supported financially by grants from the Spanish (AGL2015-65046-C2-1-R, AGL2015-65560-R, and PCIN-2013-065) and Basque (2014111157) governments.

Compliance with Ethical Standards

This study was approved by the Ethics Committee for Animal Experiments of the University of Zaragoza (permit number PI32/13) and was performed in accordance with the recommendations for the care and use of experimental animals and with Spanish national law (R.D. 1201/05).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2017_832_MOESM1_ESM.pdf (985 kb)
ESM 1 (PDF 985 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Alicia Otero
    • 1
  • Rosa Bolea
    • 1
  • Carlos Hedman
    • 1
  • Natalia Fernández-Borges
    • 2
  • Belén Marín
    • 1
  • Óscar López-Pérez
    • 1
    • 3
  • Tomás Barrio
    • 1
  • Hasier Eraña
    • 2
  • Manuel A. Sánchez-Martín
    • 4
    • 5
  • Marta Monzón
    • 1
  • Juan José Badiola
    • 1
  • Joaquín Castilla
    • 2
    • 6
  1. 1.Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Facultad de VeterinariaUniversidad de ZaragozaZaragozaSpain
  2. 2.CIC bioGUNE, Parque Tecnológico de BizkaiaDerioSpain
  3. 3.Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de VeterinariaUniversidad de ZaragozaZaragozaSpain
  4. 4.Servicio de Transgénesis, NucleusUniversidad de SalamancaSalamancaSpain
  5. 5.IBSAL, Instituto de Investigación Biomédica de SalamancaSalamancaSpain
  6. 6.IKERBASQUE, Basque Foundation for ScienceBilbaoSpain

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