title: Plasma membrane invaginations containing clusters of full-length PrPSc are an early form of prion-associated neuropathology in vivo.
abstract: During prion disease, cellular prion protein (PrP(C)) is refolded into a pathogenic isoform (PrP(Sc)) that accumulates in the central nervous system and causes neurodegeneration and death. We used immunofluorescence, quantitative cryo-immunogold EM, and tomography to detect nascent, full-length PrP(Sc) in the hippocampus of prion-infected mice from early preclinical disease stages onward. Comparison of uninfected and infected brains showed that sites containing full-length PrP(Sc) could be recognized in the neuropil by bright spots and streaks of immunofluorescence on semi-thin (200-nm) sections, and by clusters of cryo-immunogold EM labeling. PrP(Sc) was found mainly on neuronal plasma membranes, most strikingly on membrane invaginations and sites of cell-to-cell contact, and was evident by 65 days postinoculation, or 54% of the incubation period to terminal disease. Both axons and dendrites in the neuropil were affected. We hypothesize that closely apposed plasma membranes provide a favorable environment for prion conversion and intercellular prion transfer. Only a small proportion of clustered PrP immunogold labeling was found at synapses, indicating that synapses are not targeted specifically in prion disease.
authors.affiliation: Department of Cell Biology II, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Susan F
authors.initials: SF
authors.lastname: Godsave
authors.forename: Holger
authors.initials: H
authors.lastname: Wille
authors.forename: Jason
authors.initials: J
authors.lastname: Pierson
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D001923:Brain Chemistry; D002450:Cell Communication; D002462:Cell Membrane / Q000737:chemistry* / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology*
chemical_list: D018620:PrPSc Proteins