title: Thermodynamic stabilization of the folded domain of prion protein inhibits prion infection in vivo.
abstract: Prion diseases, or transmissible spongiform encephalopathies (TSEs), are associated with the conformational conversion of the cellular prion protein, PrP(C), into a protease-resistant form, PrP(Sc). Here, we show that mutation-induced thermodynamic stabilization of the folded, α-helical domain of PrP(C) 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 PrP(C)→PrP(Sc) conformational transition, and they suggest an approach to the treatment of prion diseases.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. qxk2@case.edu
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Mills
authors.forename: Bishwajit
authors.initials: B
authors.lastname: Kundu
authors.forename: Xinyi
authors.initials: X
authors.lastname: Li
authors.forename: Liuting
authors.initials: L
authors.lastname: Qing
authors.forename: Krystyna
authors.initials: K
authors.lastname: Surewicz
authors.forename: Ignazio
authors.initials: I
authors.lastname: Cali
authors.forename: Shenghai
authors.initials: S
authors.lastname: Huang
authors.forename: Mengjie
authors.initials: M
authors.lastname: Zheng
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Swietnicki
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sönnichsen
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.forename: Witold K
authors.initials: WK
authors.lastname: Surewicz
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D011328:Prions