title: De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis.
abstract: Most transmissible spongiform encephalopathies arise either spontaneously or by infection. Mutations of PRNP, which encodes the prion protein, PrP, segregate with phenotypically similar diseases. Here we report that moderate overexpression in transgenic mice of mPrP(170N,174T), a mouse PrP with two point mutations that subtly affect the structure of its globular domain, causes a fully penetrant lethal spongiform encephalopathy with cerebral PrP plaques. This genetic disease was reproduced with 100% attack rate by intracerebral inoculation of brain homogenate to tga20 mice overexpressing WT PrP, and from the latter to WT mice, but not to PrP-deficient mice. Upon successive transmissions, the incubation periods decreased and PrP became more protease-resistant, indicating the presence of a strain barrier that was gradually overcome by repeated passaging. This shows that expression of a subtly altered prion protein, with known 3D structure, efficiently generates a prion disease.
authors.affiliation: UniversitätsSpital Zürich, Institute of Neuropathology, CH-8091 Zürich, Switzerland.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Sigurdson
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
authors.forename: Simone
authors.initials: S
authors.lastname: Hornemann
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manco
authors.forename: Petra
authors.initials: P
authors.lastname: Schwarz
authors.forename: David
authors.initials: D
authors.lastname: Ott
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Pawel P
authors.initials: PP
authors.lastname: Liberski
authors.forename: Christian
authors.initials: C
authors.lastname: Julius
authors.forename: Jeppe
authors.initials: J
authors.lastname: Falsig
authors.forename: Lothar
authors.initials: L
authors.lastname: Stitz
authors.forename: Kurt
authors.initials: K
authors.lastname: Wüthrich
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D018014:Gene Transfer Techniques; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation; D017096:Prion Diseases / Q000209:etiology* / Q000473:pathology / Q000635:transmission; D011328:Prions / Q000008:administration & dosage / Q000235:genetics*; D011487:Protein Conformation
chemical_list: D011328:Prions