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J. Biol. Chem., Vol. 282, Issue 49, 35855-35867, December 7, 2007

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Influence of Water, Fat, and Glycerol on the Mechanism of Thermal Prion Inactivation^*

Henrik Müller, Lothar Stitz, Holger Wille^¶||, Stanley B. Prusiner^¶||**1, and Detlev Riesner²

From the Institut für Physikalische Biologie, Heinrich Heine-Universität Düsseldorf, D-40225 Düsseldorf, Germany, Friedrich Loeffler-Institut, Bundesforschungsinstitut für Tiergesundheit, D-72076 Tübingen, Germany, and the ^¶Institute for Neurodegenerative Diseases, the ^||Department of Neurology and the ^**Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143

Extending the recent analysis of the safety of industrial bovine fat-derived products for human consumption (Müller, H., Stitz, L., and Riesner, D. (2006) Eur. J. Lip. Sci. Technol. 108, 812-826), we investigated systematically the effects of fat, fatty acids, and glycerol on the heat destruction of prions. Prion destruction was qualitatively and quantitatively evaluated in PrP 27-30, or prion rods, by the inactivation of infectivity as well as by the degradation of the polypeptide backbone. Under all conditions analyzed, inactivation of prion infectivity was achieved more efficiently than backbone degradation by several orders of magnitude. The presence of fat enhanced prion inactivation and offers a mild treatment for prion decontamination. In contrast, the presence of fat, fatty acids, and especially glycerol protected the PrP 27-30 backbone against heat-induced degradation. Glycerol also protected against heat-induced inactivation of prion infectivity. A phase distribution analysis demonstrated that prions migrated to the interphase of a fat/water mixture at room temperature and accumulated in the water phase at higher temperatures. In a systematic study of the mechanism of prion destruction, we found an intermediate structure of PrP that has fewer fibrils in β-sheet formation, lower resistance to protease digestion, greater aggregation, and reduced solubility compared with PrP 27-30 but retains residual infectivity. These findings suggest that prion infectivity depends on β-sheet-rich fibrillar structure and that inactivation proceeds in a stepwise manner, which explains the tailing effect frequently observed during inactivation.

Received for publication, August 17, 2007

^* This work was supported by grants from the European Oleochemicals and Allied Products Group, NeuroPrion, Network of Excellence, National Institutes of Health Grants AG02132 and AG10770, the Sherman Fairchild Foundation, and a gift from the G. Harold and Leila Y. Mathers Charitable Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Has financial interest in InPro Biotechnology, Inc.

² To whom correspondence should be addressed: Institut für Physikalische Biologie, Heinrich Heine-Universität Düsseldorf, Gebäude 26.12. U1, Universitätsstrasse 1, D-40225 Düsseldorf, Germany. Tel.: 49-211-81-14840; Fax: 49-211-81-15167; E-mail: riesner{at}biophys.uni-duesseldorf.de.

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