Changes in the localization of brain prion proteins during scrapie infection

Abstract

Prion proteins (PrP) were localized in the brains of normal and scrapie-infected hamsters by immunohistochemistry and Western blotting. PrP monoclonal antibodies and monospecific anti-PrP peptide sera, which react with both the cellular (Prp^C) and scrapie (PrP^Sc) isofoms of the prion protein, were used to locate PrP in tissue sections. In normal hamsters, PrP^C was located primarily in nerve cell bodies throughout the CNS; whereas, in the terminal stages of scrapie, PrP immunoreactivity was shifted to the neuropil and was absent from most nerve cell bodies. Prion proteins were not uniformly dispersed throughout the gray matter of scrapie-infected hamster brains; rather, they were concentrated in those regions that exhibited spongiform degeneration and reactive astrogliosis. Since earlier studies showed that the level of PrP^C remains constant during scrapie infection as measured in whole brain homogenates and no antibodies are presently available that can distinguish PrP^C from PrP^Sc, we analyzed individual brain regions by Western blotting. Analysis of proteinase K-digested homogenates of dissected brain regions showed that most of the regional changes in PrP immunoreactivity that are seen during scrapie infection are due to the accumulation of PrP^Sc. These observations indicate that the tissue pathology of scrapie can be directly correlated with the accumulation of PrP^Sc in the neuropil, and they suggest that the synthesis and distribution of the prion protein has a central role in the pathogenesis of this disorder.