Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases

UMMS Affiliation

Wellstone Center for FSHD; Department of Cell and Developmental Biology



Document Type


Medical Subject Headings

Animals; Blotting, Western; Brain; Codon; Creutzfeldt-Jakob Syndrome; *Disease Models, Animal; Female; Humans; Immunohistochemistry; Insomnia, Fatal Familial; Kaplan-Meier Estimate; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Genetic; *Mutation; Phenotype; Prion Diseases; Prions; Proliferating Cell Nuclear Antigen


Cell Biology | Developmental Biology | Molecular Biology | Molecular Genetics | Musculoskeletal Diseases | Nervous System Diseases


In man, mutations in different regions of the prion protein (PrP) are associated with infectious neurodegenerative diseases that have remarkably different clinical signs and neuropathological lesions. To explore the roots of this phenomenon, we created a knock-in mouse model carrying the mutation associated with one of these diseases [Creutzfeldt-Jakob disease (CJD)] that was exactly analogous to a previous knock-in model of a different prion disease [fatal familial insomnia (FFI)]. Together with the WT parent, this created an allelic series of three lines, each expressing the same protein with a single amino acid difference, and with all native regulatory elements intact. The previously described FFI mice develop neuronal loss and intense reactive gliosis in the thalamus, as seen in humans with FFI. In contrast, CJD mice had the hallmark features of CJD, spongiosis and proteinase K-resistant PrP aggregates, initially developing in the hippocampus and cerebellum but absent from the thalamus. A molecular transmission barrier protected the mice from any infectious prion agents that might have been present in our mouse facility and allowed us to conclude that the diseases occurred spontaneously. Importantly, both models created agents that caused a transmissible neurodegenerative disease in WT mice. We conclude that single codon differences in a single gene in an otherwise normal genome can cause remarkably different neurodegenerative diseases and are sufficient to create distinct protein-based infectious elements.

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Citation: Jackson WS, Borkowski AW, Watson NE, King OD, Faas H, Jasanoff A, Lindquist S. Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases. Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14759-64. doi: 10.1073/pnas.1312006110. Link to article on publisher's site

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