An inter-domain regulatory mechanism controls toxic activities of PrP^C

The normal function of PrP^C, the cellular prion protein, has remained mysterious since its first description over 30 years ago. Amazingly, although complete deletion of the gene encoding PrP^C has little phenotypic consequence, expression in transgenic mice of PrP molecules carrying certain internal deletions produces dramatic neurodegenerative phenotypes. In our recent paper, ¹ we have demonstrated that the flexible, N-terminal domain of PrP^C 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^Sc and possibly other protein aggregates, and could play a role in the physiological activity of PrP^C. These results also provide a warning about the potential toxic side effects of PrP-directed antibody therapies for prion and Alzheimer's diseases.