Thermodynamic Stabilization of the Folded Domain of Prion Protein Inhibits Prion Infection in Vivo

• Stabilization of an α-helical domain of PrP inhibits prion protein conversion in vitro
• Transgenic mice expressing a superstable PrP variant are resistant to prion infection
• The findings suggest a strategy for pharmacological intervention in prion diseases

SummaryPrion diseases, or transmissible spongiform encephalopathies (TSEs), are associated with the conformational conversion of the cellular prion protein, PrPC, into a protease-resistant form, PrPSc. Here, we show that mutation-induced thermodynamic stabilization of the folded, α-helical domain of PrPC has a dramatic inhibitory effect on the conformational conversion of prion protein in vitro, as well as on the propagation of TSE disease in vivo. Transgenic mice expressing a human prion protein variant with increased thermodynamic stability were found to be much more resistant to infection with the TSE agent than those expressing wild-type human prion protein, in both the primary passage and three subsequent subpassages. These findings not only provide a line of evidence in support of the protein-only model of TSEs but also yield insight into the molecular nature of the PrPC→PrPSc conformational transition, and they suggest an approach to the treatment of prion diseases.

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