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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

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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.

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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.

Funding

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.

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Authors and Affiliations

  1. Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Facultad de Veterinaria, IA2, IIS, Universidad de Zaragoza, Zaragoza, Spain

    Alicia Otero, Carlos Hedman, Belén Marín, Marta Monzón, Juan José Badiola & Rosa Bolea

  2. CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Bizkaia, Spain

    Natalia Fernández-Borges, Hasier Eraña & Joaquín Castilla

  3. Servicio de Transgénesis, Nucleus, Universidad de Salamanca, Salamanca, Spain

    Manuel A. Sánchez-Martín

  4. IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain

    Manuel A. Sánchez-Martín

  5. Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy

    Romolo Nonno

  6. IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain

    Joaquín Castilla

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  1. Alicia Otero
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Contributions

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.

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Correspondence to Rosa Bolea or Joaquín Castilla.

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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).

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Otero, A., Hedman, C., Fernández-Borges, N. et al. 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. Mol Neurobiol 56, 6501–6511 (2019). https://doi.org/10.1007/s12035-019-1535-0

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