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Towards authentic transgenic mouse models of heritable PrP prion diseases

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Abstract

Attempts to model inherited human prion disorders such as familial Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker (GSS) disease, and fatal familial insomnia (FFI) using genetically modified mice have produced disappointing results. We recently demonstrated that transgenic (Tg) mice expressing wild-type bank vole prion protein (BVPrP) containing isoleucine at polymorphic codon 109 develop a spontaneous neurodegenerative disorder that exhibits many of the hallmarks of prion disease. To determine if mutations causing inherited human prion disease alter this phenotype, we generated Tg mice expressing BVPrP containing the D178N mutation, which causes FFI; the E200K mutation, which causes familial CJD; or an anchorless PrP mutation similar to mutations that cause GSS. Modest expression levels of mutant BVPrP resulted in highly penetrant spontaneous disease in Tg mice, with mean ages of disease onset ranging from ~120 to ~560 days. The brains of spontaneously ill mice exhibited prominent features of prion disease-specific neuropathology that were unique to each mutation and distinct from Tg mice expressing wild-type BVPrP. An ~8-kDa proteinase K-resistant PrP fragment was found in the brains of spontaneously ill Tg mice expressing either wild-type or mutant BVPrP. The spontaneously formed mutant BVPrP prions were transmissible to Tg mice expressing wild-type or mutant BVPrP as well as to Tg mice expressing mouse PrP. Thus, Tg mice expressing mutant BVPrP exhibit many of the hallmarks of heritable prion disorders in humans including spontaneous disease, protease-resistant PrP, and prion infectivity.

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Acknowledgments

We would like to thank the staff at the Hunters Point Animal Facility for their contributions to this project. The authors are grateful to Romolo Nonno for sharing his unpublished data and for helping us uncover the PK-resistant PrP fragment in our spontaneously ill mice.

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Authors and Affiliations

  1. Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA

    Joel C. Watts, Kurt Giles, Smita Patel, Abby Oehler, Marta Gavidia, Sumita Bhardwaj, Joanne Lee & Stanley B. Prusiner

  2. Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA

    Joel C. Watts, Kurt Giles & Stanley B. Prusiner

  3. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94143, USA

    Stanley B. Prusiner

  4. Tanz Centre for Research in Neurodegenerative Diseases, Department of Biochemistry, University of Toronto, Toronto, ON, M5T 2S8, Canada

    Joel C. Watts & Matthew E. C. Bourkas

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Correspondence to Stanley B. Prusiner.

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Funding

This work was supported by grants from the National Institutes of Health (AG021601, AG002132, and AG010770), the Sherman Fairchild Foundation, and the Glenn Foundation for Medical Research (S.B.P.), and by awards from the Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-05112) and the CJD Foundation (J.C.W.).

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Watts, J.C., Giles, K., Bourkas, M.E.C. et al. Towards authentic transgenic mouse models of heritable PrP prion diseases. Acta Neuropathol 132, 593–610 (2016). https://doi.org/10.1007/s00401-016-1585-6

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