title: Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases.
abstract: 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.
authors: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors: Walker S
authors: WS
authors: Jackson
authors: Andrew W
authors: AW
authors: Borkowski
authors: Nicki E
authors: NE
authors: Watson
authors: Oliver D
authors: OD
authors: King
authors: Henryk
authors: H
authors: Faas
authors: Alan
authors: A
authors: Jasanoff
authors: Susan
authors: S
authors: Lindquist
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003062:Codon / Q000235:genetics*; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000378:metabolism / Q000635:transmission; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D034062:Insomnia, Fatal Familial / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism / Q000635:transmission; D011328:Prions / Q000235:genetics* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism
chemical_list: D003062:Codon; D011328:Prions; D018809:Proliferating Cell Nuclear Antigen
keywords: neurodegeneration; protein aggregation; protein misfolding; transgenic mice
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