Transmissible spongiform encephalopathies (TSEs) are also known as prion diseases. The unusual infectious agent is composed largely, if not entirely, of a proteinase resistant aberrantly folded isoform of the prion protein (PrPSc). PrPSc, through an unknown mechanism, is believed to impose its aberrant conformation onto the host-encoded cellular prion protein, PrPC. The infectious particle is designated a "prion", an acronym for proteinaceous infectious particle, to distinguish it from conventional pathogens such as viruses and bacteria. The essential role of PrPC in the pathogenesis of prion diseases motivated the detailed study of the cellular processing, turnover and release of bovine PrPC (boPrPC) performed in this thesis. BoPrPC was found to be subjected to two distinct proteolytic cleavage events, generating an N-terminal and a C-terminal boPrPC fragment. Both PrP fragments were released from the cell. Moreover, in normal bovine brain a C-terminal fragment was found, suggesting that similar proteolytic processing events occur in vivo. The finding that boPrPC in addition to a protease-mediated release also was released in association with exosomes, provide important information in relation to functional aspects of PrPC and possible roles of exosome-associated PrP in pathogenesis of prion diseases. Taken together, these results indicate that release of boPrPC from cells represent an important step in the normal cellular processing of boPrPC. Nor98 is a recently recognised prion disease in sheep. The molecular characterization of the Nor98 prion showed that the unique PK-resistant PrP fragments present in Nor98-affected sheep display striking similarities to those reported from individuals affected by the human prion disorder Gerstmann-Sträussler-Scheinker syndrome (GSS). Interestingly, GSS is always associated with amino acid substitutions in the PrP. Differently, no disease-causing changes in the PrP of Nor98-affected sheep have been found in the affected sheep in Sweden. These findings together with observations of a distinct epidemiology, suggest that Nor98 could be the result of a spontaneous conversion of PrPC into PrPSc, similar to that proposed for sporadic Creutzfeldt-Jakob disease and sporadic fatal insomnia
