Technical Abstract: Transmission studies in transmissible spongiform encephalopathies (TSE's) have become increasingly important due to the possible transmission of bovine spongiform encephalopathy (BSE) to humans in the form of new variant Creutzfeldt-Jacob disease (V-CJD). Horizontal transmission is poorly understood within natural sheep scrapie. Two possible sources of horizontal transmission are the submandibular and parotid salivary glands. TSE's like natural sheep scrapie are characterized by the conversion of a normal cellular protease sensitive prion protein isoform, PrPc, to an abnormal protease resistant prion protein isoform, PrPSc. In this study, the expression of PrPc and PrPSc in the salivary glands of scrapie susceptible sheep was evaluated. PrPc mRNA was found in the salivary glands of sheep with no known previous exposure to scrapie (normal) and scrapie- infected sheep, and PrPc was found in low amounts in the salivary glands of normal sheep. Although PrPSc was not found in the salivary glands of scrapie-infected sheep, salivary gland homogenates contained proteases that degraded PrPc, but not PrPSc isolated from brain homogenates. These results suggest that protease activity in the salivary glands may regulate PrPc availability and therefore, may indirectly regulate conversion to PrPSc.