title: Spontaneous generation of anchorless prions in transgenic mice.
abstract: Some prion protein mutations create anchorless molecules that cause Gerstmann-Sträussler-Scheinker (GSS) disease. To model GSS, we generated transgenic mice expressing cellular prion protein (PrP(C)) lacking the glycosylphosphatidyl inositol (GPI) anchor, denoted PrP(ΔGPI). Mice overexpressing PrP(ΔGPI) developed a late-onset, spontaneous neurologic dysfunction characterized by widespread amyloid deposition in the brain and the presence of a short protease-resistant PrP fragment similar to those found in GSS patients. In Tg(PrP,ΔGPI) mice, disease onset could be accelerated either by inoculation with brain homogenate prepared from spontaneously ill animals or by coexpression of membrane-anchored, full-length PrP(C). In contrast, coexpression of N-terminally truncated PrP(Δ23-88) did not affect disease progression. Remarkably, disease from ill Tg(PrP,ΔGPI) mice transmitted to mice expressing wild-type PrP(C), indicating the spontaneous generation of prions.
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Stöhr
authors.forename: Joel C
authors.initials: JC
authors.lastname: Watts
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
authors.forename: Abby
authors.initials: A
authors.lastname: Oehler
authors.forename: Azucena
authors.initials: A
authors.lastname: Lemus
authors.forename: Hoang-Oanh B
authors.initials: HO
authors.lastname: Nguyen
authors.forename: Joshua
authors.initials: J
authors.lastname: Sussman
authors.forename: Holger
authors.initials: H
authors.lastname: Wille
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.forename: Kurt
authors.initials: K
authors.lastname: Giles
mesh_terms: D000682:Amyloid / Q000648:ultrastructure*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D018604:Epitope Mapping; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D017261:Glycosylphosphatidylinositols / Q000172:deficiency*; D006652:Histological Techniques; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding
chemical_list: D000682:Amyloid; D017261:Glycosylphosphatidylinositols; D018621:PrPC Proteins