Update on Creutzfeldt-Jakob disease

Abstract

Prion diseases are transmissible fatal neurodegenerative disorders in which infectivity is associated with the accumulation of PrP(Sc), a disease-related isoform of normal cellular prion protein. The recent emergence of variant Creutzfeldt-Jakob disease has led to major public health concerns, and the need for the development of effective treatments. As PrP(Sc) is associated both with pathology and infectivity, therapeutic approaches to date have largely aimed at preventing its accumulation, but this strategy has produced only modest results in animal models. The link between PrP(Sc) and neurotoxicity is unclear, and alternative pathological processes need to be considered. Here we focus on the latest progress in therapeutic strategies and potential mechanisms of prion neurotoxicity. Passive immunisation with anti-prion protein antibodies prevents peripheral prion replication and blocks progression to clinical disease in peripherally infected mice. A new approach, in which neuronal cellular prion protein is depleted in mice with established neuroinvasive prion infection, prevents the onset of clinical disease, blocks neuronal cell loss and reverses early spongiform pathology. This dramatic protective effect occurs despite the continued build-up of extraneuronal PrP(Sc) and continued replication of prion infectivity, effectively producing a sub-clinical state. New insights into the mechanisms of neurotoxicity in prion diseases support the concept that PrP(Sc) itself is not directly neurotoxic. They suggest that neuronal prion propagation results in the production of a toxic intermediate or depletion of a key constituent. Prevention of the formation of such a species rather than PrP(Sc) accumulation itself is a clear target for prion therapeutics.