title: Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice.
abstract: The absence of infectivity-associated, protease-resistant prion protein (PrP(Sc)) in the brains of spontaneously sick transgenic (Tg) mice overexpressing PrP linked to Gerstmann-Sträussler Scheinker syndrome, and the failure of gene-targeted mice expressing such PrP to develop disease spontaneously, challenged the concept that mutant PrP expression led to spontaneous prion production. Here, we demonstrate that disease in overexpressor Tg mice is associated with accumulation of protease-sensitive aggregates of mutant PrP that can be immunoprecipitated by the PrP(Sc)-specific monoclonal antibody designated 15B3. Whereas Tg mice expressing multiple transgenes exhibited accelerated disease when inoculated with disease-associated mutant PrP, Tg mice expressing mutant PrP at low levels failed to develop disease either spontaneously or following inoculation. These studies indicate that inoculated mutant PrP from diseased mice promotes the aggregation and accumulation of pre-existing pathological forms of mutant PrP produced as a result of transgene overexpression. Thus, while pathological mutant PrP possesses a subset of PrP(Sc) characteristics, we now show that the attribute of prion transmission suggested by previous studies is more accurately characterized as disease acceleration.
authors.affiliation: Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Karah E
authors.initials: KE
authors.lastname: Nazor
authors.forename: Franziska
authors.initials: F
authors.lastname: Kuhn
authors.forename: Tanya
authors.initials: T
authors.lastname: Seward
authors.forename: Mike
authors.initials: M
authors.lastname: Green
authors.forename: Daniel
authors.initials: D
authors.lastname: Zwald
authors.forename: Mario
authors.initials: M
authors.lastname: Pürro
authors.forename: Jaqueline
authors.initials: J
authors.lastname: Schmid
authors.forename: Karin
authors.initials: K
authors.lastname: Biffiger
authors.forename: Aisling M
authors.initials: AM
authors.lastname: Power
authors.forename: Bruno
authors.initials: B
authors.lastname: Oesch
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Raeber
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001921:Brain / Q000378:metabolism; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D018620:PrPSc Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D000911:Antibodies, Monoclonal; D018620:PrPSc Proteins