An inter-domain regulatory mechanism controls toxic activities of PrP.

The normal function of PrP, the cellular prion protein, has remained mysterious since its first description over 30 years ago. Amazingly, although complete deletion of the gene encoding PrP has little phenotypic consequence, expression in transgenic mice of PrP molecules carrying certain internal deletions produces dramatic neurodegenerative phenotypes. In our recent paper, we have demonstrated that the flexible, N-terminal domain of PrP possesses toxic effector functions, which are regulated by a docking interaction with the structured, C-terminal domain. Disruption of this inter-domain interaction, for example by deletions of the hinge region or by binding of antibodies to the C-terminal domain, results in abnormal ionic currents and degeneration of dendritic spines in cultured neuronal cells. This mechanism may contribute to the neurotoxicity of PrP and possibly other protein aggregates, and could play a role in the physiological activity of PrP. These results also provide a warning about the potential toxic side effects of PrP-directed antibody therapies for prion and Alzheimer's diseases.