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

• Published in: Cell reports (Cambridge) 2013-07, Vol.4 (2), p.248-254
• Main Authors: Kong, Qingzhong, Mills, Jeffrey L., Kundu, Bishwajit, Li, Xinyi, Qing, Liuting, Surewicz, Krystyna, Cali, Ignazio, Huang, Shenghai, Zheng, Mengjie, Swietnicki, Wieslaw, Sönnichsen, Frank D., Gambetti, Pierluigi, Surewicz, Witold K.
• Format: Article
• Language: English
• Subjects: Animals; Humans; Mice; Mice, Transgenic; Models, Molecular; Prion Diseases - metabolism; Prions - chemistry; Prions - genetics; Prions - metabolism; Protein Structure, Secondary; Thermodynamics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.06.030

Prion 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. [Display omitted] •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 Prion diseases are associated with the conformational conversion of the cellular prion protein, PrPC, into a β-sheet-rich aggregated form, PrPSc. In this study, Surewicz, Kong, and colleagues show that mutation-induced thermodynamic stabilization of the native α-helical domain of PrPC suppresses the conversion reaction in vitro and inhibits prion propagation in transgenic mice. These findings provide insight into the molecular basis of prion diseases and suggest an approach for pharmacological intervention in these disorders.