P3–372: Oxidative stress and prion protein mutations

Prion diseases, devastating, invariably fatal diseases of the central nervous system, are the result of sporadic, inherited, or infectious causes. The initiating events in the sporadic and inherited diseases are currently unknown although the major risk factor is ageing since most types of prion diseases affect the aged human population. Our hypothesis is that mutations in the prion protein, which are associated with the inherited forms of prion disease, compromise the role of prion protein in the response to oxidative stress which in turn leaves the prion protein vulnerable to redox sensitive post–translational modification. These modifications may make the prion protein more susceptible to the pathogenic conversion characteristic of prion disease. Indeed, oxidative stress is increased by age and oxidative stress is known to be increased in many different types of prion diseases such as scrapie, CJD and FFI. To test our hypothesis, using known pathogenic mutations in the human prion protein, which are fully penetrant, we have investigated the role of the mutations in leading to the development of disease. Taking advantage of well characterized cell models, we characterized the effect of oxidative stress on cells expressing mutant prion protein. In addition, we monitored the change in protease resistance of the prion protein after oxidative challenge. We found that the expression of mutant prion protein, but not wild–type prion protein, increased the vulnerability to hydrogen peroxide–mediated oxidative stress. These results suggest that the pathogenic mutation in prion disease may contribute the initiation and/or progression of the disease by increasing the vulnerability to oxidative stress. Therefore, our study is helping to define the factors that lead to initiation and progression of the disease process.