It has been suggested that antibodies against prion protein might have therapeutic value. However, a study in this week's Nature shows that many antiprion antibodies cause neurotoxicity and also reveals the mechanism underlying these observations.
The prion protein - which in a misfolded form is associated with neurotoxic effects such as those seen in Creutzfeldt-Jakob disease - contains a globular domain and a flexible tail. Aguzzi and colleagues show that antibodies against the globular domain cause neurotoxicity in mice and cerebellar cultured slices. This neurodegeneration is accompanied by a burst of reactive oxygen species, suppressed by antioxidants, and toxicity is dependent on the presence of the superoxide-producing enzyme NOX2. Specific amino acid repeats within the flexible domain seem to be required for this antibody-mediated toxicity, and, remarkably, antibodies against these repeats are able to prolong life in mice expressing a toxic mutant prion protein, suggesting that in this mouse model of prion disease, toxicity is mediated by the flexible tail as well.
The authors conclude that the cellular prion protein consists of two functionally distinct modules, with the globular domain and the flexible tail exerting regulatory and executive functions, respectively.