The Roslin Institute
Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, such as scrapie in sheep and vCJD in man are fatal neurodegenerative disorders characterised by prion protein misfolding and aggregation in the brain. My group investigates the general and species-specific mechanisms that link susceptibility of classical and atypical forms of TSEs to genetic variation of the PRNP gene encoding the prion or PrP protein. This will enable us to perform better prediction of host disease response and to improve risk assessments and breeding strategies. While scrapie eradication through PRNP breeding has been successfully applied to sheep populations throughout the world, other livestock and free-ranging species with TSE disease outbreaks have not yet benefitted from similar genetic selection programs. We are currently exploring options of genetic control in goat scrapie and chronic wasting disease in American deer and study the susceptibility of scavengers and carnivores to prion agents.
Another aim of my group is to understand the molecular mechanisms that link the prion protein gene family, particularly PRNP (PrP) and SPRN (Shadoo) with TSEs. The expression level of the PrP protein is of crucial importance in TSE disease and appears also to have a significant role in neuronal survival. The role of shadoo protein may be similar to PrP but is as yet poorly understood. Both proteins are processed during maturation into various isoforms and fragments, which are likely to have distinct biological roles in normal health and in prion disease. Our research has recently shown that this protein processing is significantly modulated by PRNP genetics. Similarly, misfolding of the prion protein is modified and inhibited by PrP protein fragments. The search for genes controlling the expression and processing of prion protein in TSE susceptible and resistant species is therefore our current focus.