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Acta Neuropathol. 2016 Oct;132(4):593-610. doi: 10.1007/s00401-016-1585-6. Epub 2016 Jun 28.

Towards authentic transgenic mouse models of heritable PrP prion diseases.

Author information

1
Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA.
2
Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA.
3
Tanz Centre for Research in Neurodegenerative Diseases, Department of Biochemistry, University of Toronto, Toronto, ON, M5T 2S8, Canada.
4
Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA. stanley.prusiner@ucsf.edu.
5
Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA. stanley.prusiner@ucsf.edu.
6
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94143, USA. stanley.prusiner@ucsf.edu.

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.

KEYWORDS:

Creutzfeldt–Jakob; Fatal familial insomnia; Gerstmann–Sträussler–Scheinker; Prion; Transgenic mice

PMID:
27350609
PMCID:
PMC5152593
DOI:
10.1007/s00401-016-1585-6
[Indexed for MEDLINE]
Free PMC Article

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