title: Soluble dimeric prion protein binds PrP(Sc) in vivo and antagonizes prion disease.
abstract: Conversion of cellular prion protein (PrP(C)) into a pathological conformer (PrP(Sc)) is thought to be promoted by PrP(Sc) in a poorly understood process. Here, we report that in wild-type mice, the expression of PrP(C) rendered soluble and dimeric by fusion to immunoglobulin Fcgamma (PrP-Fc(2)) delays PrP(Sc) accumulation, agent replication, and onset of disease following inoculation with infective prions. In infected PrP-expressing brains, PrP-Fc(2) relocates to lipid rafts and associates with PrP(Sc) without acquiring protease resistance, indicating that PrP-Fc(2) resists conversion. Accordingly, mice expressing PrP-Fc(2) but lacking endogenous PrP(C) are resistant to scrapie, do not accumulate PrP-Fc(2)(Sc), and do not transmit disease to others. These results indicate that various PrP isoforms engage in a complex in vivo, whose distortion by PrP-Fc(2) affects prion propagation and scrapie pathogenesis. The unique properties of PrP-Fc(2) suggest that soluble PrP derivatives may represent a new class of prion replication antagonists.
authors.affiliation: Institute of Neuropathology, Schmelzbergstrasse, University Hospital of Zürich, Zürich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Meier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Genoud
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Manuela
authors.initials: M
authors.lastname: Maissen
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Andreas
authors.initials: A
authors.lastname: Zurbriggen
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Raeber
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000502:physiology; D010450:Endopeptidases / Q000378:metabolism; D008024:Ligands; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011233:Precipitin Tests; D017096:Prion Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000472:pathogenicity; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D012608:Scrapie / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D020033:Protein Isoforms; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D010450:Endopeptidases