title: Towards authentic transgenic mouse models of heritable PrP prion diseases.
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.
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA.|Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA.|Tanz Centre for Research in Neurodegenerative Diseases, Department of Biochemistry, University of Toronto, Toronto, ON, M5T 2S8, Canada.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Watts
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA.|Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Giles
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, Department of Biochemistry, University of Toronto, Toronto, ON, M5T 2S8, Canada.
authors.forename: Matthew E C
authors.initials: ME
authors.lastname: Bourkas
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Patel
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA.
authors.forename: Abby
authors.initials: A
authors.lastname: Oehler
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Gavidia
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Bhardwaj
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lee
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94143-0518, USA. stanley.prusiner@ucsf.edu.|Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA. stanley.prusiner@ucsf.edu.|Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94143, USA. stanley.prusiner@ucsf.edu.
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D016098:Gerstmann-Straussler-Scheinker Disease / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D018620:PrPSc Proteins
keywords: Creutzfeldt–Jakob; Fatal familial insomnia; Gerstmann–Sträussler–Scheinker; Prion; Transgenic mice