Prion Protein Self-Interactions: a gateway to novel therapeutic strategies?

Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are unique disorders that are not caused by infectious micro-organisms (bacteria or fungi), viruses or parasites, but rather seems to be the result of an infectious protein. TSEs are comprised of fatal neurodegenerative disorders affecting both human and animals. Prion diseases cause sponge-like degeneration of neuronal tissue and include (among others) Creutzfeldt-Jacob disease in humans, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. TSEs are characterized by formation and accumulation of transmissible (infectious) disease associated protease resistant prion protein (PrPSc) mainly in tissues of the central nervous system. The exact molecular processes behind PrPC into PrPSc conversion are not clearly understood. Correlations between prion protein polymorphisms and disease have been found, however in what way these polymorphisms influence the conversion processes remains an enigma; is stabilization or destabilization of the prion protein the basis for a higher conversion propensity? Apart from the disease associated polymorphisms of the prion protein, the molecular processes underlying conversion are not understood. There are some notions as to which regions of the prion protein are involved in refolding of PrPC into PrPSc and were the most drastic structural changes take place. Direct interactions between PrPC molecules and/or PrPSc are likely at the basis of conversion, however which specific amino acid domains are involved and to what extent these domains contribute to conversion resistance/sensitivity of the prion protein or the species barrier is still unknown. Furthermore the physiological function of PrPC is also still enigmatic; does refolding of the protein play a role in its function? How does interfering with PrPC function by therapeutic treatment affect the treated individual? Until such questions are answered it seems prudent to design therapeutic therapies that circumvent total ablation of PrPC or at least focus should be on strategies that allow for retention or reacquiring of PrPC physiological function. Several basic questions remain to be answered and this thesis aimed to study the processes involved in PrPC to PrPSc conversion. First the influence of disease associated polymorphisms on binding and/or conversion was studied. Based on these results this thesis further aimed to determine which specific amino acid sequences (domains) are involved in PrP interaction and how these specific interaction domains influence conversion of PrPC into PrPSc. Answering these questions will allow for a more detailed understanding of the conversion processes, which in turn should allow for improvement of currently available therapeutics, as well as provide clues for designing novel therapeutic compounds or strategies