Regional heterogeneity of cellular prion protein isoforms in the mouse brain

Prion diseases are a group of invariably fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans, scrapie in sheep and goats, and bovine spongiform encephalopathy in cattle. The infectious agent or prion is largely composed of an abnormal isoform (PrP^sc) of a host encoded normal cellular protein (PrP^c). The conversion of PrP^c to PrP^sc is a dynamic process and, for reasons that are not clear, the distribution of spongiform change and PrP^sc deposition varies among prion strains. An obvious explanation for this would be that the transformation efficiency in any given brain region depends on favourable interactions between conformations of PrP^c and the prion strain being propagated within it. However, identification of specific PrP^c conformations has until now been hampered by a lack of suitable panels of antibodies that discriminate PrP^c subspecies under native conditions. In this study, we show that monoclonal antibodies raised against recombinant human prion protein folded into α or β conformations exhibit striking heterogeneity in their specificity for truncations and glycoforms of mouse brain PrP^c. We then show that some of these PrP^c isoforms are expressed differentially in certain mouse brain regions. This suggests that variation in the expression of PrP^c conformations in different brain regions may dictate the pattern of PrP^sc deposition and vacuolation, characteristic for different prion strains.