Prion protein self-interactions: a gateway to novel therapeutic strategies?

Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative disorders and include among others Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. The central event in disease development in TSEs is the refolding of the normal host-encoded cellular prion protein (PrP) into abnormal and disease associated prion protein. The agent is thought to consist mainly or exclusively of these pathologically folded PrP molecules. The exact molecular mechanisms underlying this process and the role of normal PrP in the conversion to pathological isoforms of PrP are still poorly understood. The highly conserved PrP gene structure and organisation however, suggests that its function is important, even though PrP knockout mice appear to develop normally. Conversion of normal PrP is initiated by interaction with abnormal PrP (or "agent") resulting in refolding of normal PrP into new pathological PrP ("agent replication"). Normal PrP was shown to interact/bind with many different molecules including metal ions, nucleic acids, several (receptor) proteins, and the prion protein itself. The processes underlying agent replication (normal to abnormal PrP conversion) are most likely initiated by selective interaction between PrP molecules and potentially influenced by chaperone molecules. Thus far no vaccine, disease reversing therapeutic compounds or strategies (cure) exists, although there are some compounds capable of slowing the progression of prion disease. Studies towards interference to date have primarily focussed on inference with the interaction between normal and pathological isoforms of PrP in order to develop therapeutic strategies or find compounds capable of inhibiting prion propagation. Most described strategies are either directed at depletion of normal PrP and thus preventing pathological PrP formation and accumulation, or are based on preventing interaction between normal and abnormal PrP. Other therapeutic strategies focus on selective (self-)interaction of normal PrP molecules. Increased understanding of these interactions and the processes in which normal PrP plays a (active) role, could potentially lead to new modes of inhibiting prion protein conversion in which the physiological function(s) of normal PrP is retained. Ultimately this may lead to therapeutic strategies that are effective not only as a prophylactic but also in later stages of prion disease development. Here we review the data underlying these PrP-based approaches.