title: Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice.
abstract: A crucial tenet of the prion hypothesis is that misfolding of the prion protein (PrP) induced by mutations associated with familial prion disease is, in an otherwise normal mammalian brain, sufficient to generate the infectious agent. Yet this has never been demonstrated. We engineered knockin mice to express a PrP mutation associated with a distinct human prion disease, fatal familial insomnia (FFI). An additional substitution created a strong transmission barrier against pre-existing prions. The mice spontaneously developed a disease distinct from that of other mouse prion models and highly reminiscent of FFI. Unique pathology was transmitted from FFI mice to mice expressing wild-type PrP sharing the same transmission barrier. FFI mice were highly resistant to infection by pre-existing prions, confirming infectivity did not arise from contaminating agents. Thus, a single amino acid change in PrP is sufficient to induce a distinct neurodegenerative disease and the spontaneous generation of prion infectivity.
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Walker S
authors.initials: WS
authors.lastname: Jackson
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Borkowski
authors.forename: Henryk
authors.initials: H
authors.lastname: Faas
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Steele
authors.forename: Oliver D
authors.initials: OD
authors.lastname: King
authors.forename: Nicki
authors.initials: N
authors.lastname: Watson
authors.forename: Alan
authors.initials: A
authors.lastname: Jasanoff
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D055879:Gene Knock-In Techniques / Q000379:methods*; D006801:Humans; D034062:Insomnia, Fatal Familial / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D011328:Prions / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D011328:Prions