Plasma membrane invaginations containing clusters of full-length PrPSc are an early form of prion-associated neuropathology in vivo

SF Godsave, H Wille, J Pierson, SB Prusiner, JPJ Peters

    Research output: Contribution to journalArticleScientificpeer-review

    16 Citations (Scopus)

    Abstract

    During prion disease, cellular prion protein (PrPC) is refolded into a pathogenic isoform (PrPSc) 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 PrPSc 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 PrPSc 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. PrPSc 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.
    Original languageEnglish
    Pages (from-to)1621-1631
    Number of pages11
    JournalNeurobiology of Aging: age-related phenomena, neurodegeneration and neuropathology
    Volume34
    Issue number6
    Publication statusPublished - 2013

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