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Molecular Neurobiology

, Volume 56, Issue 9, pp 6501–6511 | Cite as

A Single Amino Acid Substitution, Found in Mammals with Low Susceptibility to Prion Diseases, Delays Propagation of Two Prion Strains in Highly Susceptible Transgenic Mouse Models

  • Alicia Otero
  • Carlos Hedman
  • Natalia Fernández-Borges
  • Hasier Eraña
  • Belén Marín
  • Marta Monzón
  • Manuel A. Sánchez-Martín
  • Romolo Nonno
  • Juan José Badiola
  • Rosa BoleaEmail author
  • Joaquín CastillaEmail author
Article

Abstract

Specific variations in the amino acid sequence of prion protein (PrP) are key determinants of susceptibility to prion diseases. We previously showed that an amino acid substitution specific to canids confers resistance to prion diseases when expressed in mice and demonstrated its dominant-negative protective effect against a variety of infectious prion strains of different origins and characteristics. Here, we show that expression of this single amino acid change significantly increases survival time in transgenic mice expressing bank vole cellular prion protein (PrPC), which is inherently prone to misfolding, following inoculation with two distinct prion strains (the CWD-vole strain and an atypical strain of spontaneous origin). This amino acid substitution hinders the propagation of both prion strains, even when expressed in the context of a PrPC uniquely susceptible to a wide range of prion isolates. Non-inoculated mice expressing this substitution experience spontaneous prion formation, but showing an increase in survival time comparable to that observed in mutant mice inoculated with the atypical strain. Our results underscore the importance of this PrP variant in the search for molecules with therapeutic potential against prion diseases.

Keywords

Prions Prion propagation Transmissible spongiform encephalopathies Canine PrP Bank vole PrP 

Notes

Acknowledgments

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 and Patricia Piñeiro and Dr. Jan Langeveld from Central Veterinary Institute, Wageningen for kindly providing the 12B2 antibody.

Authors’ Contribution

JC and RB conceived the study; AO, CH, NFB, HE, BM, and MM performed most of the experiments; MASM and RN collaborated in the creation of the transgenic lines used; AO, HE, JJB, RB, and JC evaluated the results; AO, RB, JJB, HE, and JC wrote and reviewed the manuscript.

Funding Information

This work was supported financially by the Spanish (AGL2015-65046-C2-1-R, AGL2015-65560-R) (MINECO/FEDER) and Interreg (POCTEFA EFA148/16) grants. Alicia Otero was supported by a research grant from the Government of Aragón (C020/2014) co-financed by the European Social Fund.

Compliance with Ethical Standards

Ethics Statement

All procedures involving animals were approved by the University of Zaragoza’s Ethics Committee for Animal Experiments (permit number PI32/13) and were performed in accordance with recommendations for the care and use of experimental animals and with Spanish law (R.D. 1201/05).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1535_MOESM1_ESM.pdf (1.1 mb)
ESM 1 (PDF 1080 kb)

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Authors and Affiliations

  1. 1.Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Facultad de Veterinaria, IA2, IISUniversidad de ZaragozaZaragozaSpain
  2. 2.CIC bioGUNEParque Tecnológico de BizkaiaDerioSpain
  3. 3.Servicio de Transgénesis, NucleusUniversidad de SalamancaSalamancaSpain
  4. 4.IBSALInstituto de Investigación Biomédica de SalamancaSalamancaSpain
  5. 5.Department of Food Safety and Veterinary Public HealthIstituto Superiore di SanitàRomeItaly
  6. 6.IKERBASQUEBasque Foundation for ScienceBilbaoSpain

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