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Seeding Specificity and Ultrastructural Characteristics of Infectious Recombinant Prions

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Justin R. Piro†, Fei Wang

, Daniel J. Walsh†, Judy R. Rees‡, Jiyan Ma

, and Surachai Supattapone*†‡

^†Departments of Biochemistry, ^‡Community and Family Medicine, and ^§Medicine, Dartmouth Medical School, Hanover, New Hampshire 03755, United States

Department of Molecular and Cellular Biochemistry, Ohio State University School of Medicine, Columbus, Ohio 43210, United States

Biochemistry, 2011, 50 (33), pp 7111–7116

DOI: 10.1021/bi200786p

Publication Date (Web): July 21, 2011

Phone: (603) 650-1192. Fax: (603) 650-1193. E-mail: supattapone@dartmouth.edu.

Funding Statement

The National Institutes of Health provided financial support for this study (2R01 NS046478, R01 NS055875, R01 NS060727, and T32 AI007519).

Section:

General Biochemistry

Abstract

Infectious mouse prions can be produced from a mixture of bacterially expressed recombinant prion protein (recPrP), palmitoyloleoylphosphatidylglycerol (POPG), and RNA [Wang, F.; et al. (2010) Science327, 1132]. In contrast, amyloid fibers produced from pure recPrP without POPG or RNA (recPrP fibers) fail to infect wild type mice [Colby, D. W.; et al. (2010) PLoS Pathog. 387, e1000736]. We compared the seeding specificity and ultrastructural features of infectious recombinant prions (recPrP^Sc) with those of recPrP fibers. Our results indicate that PrP fibers are not able to induce the formation of PrP^Sc molecules from wild type mouse brain homogenate substrate in serial protein misfolding cyclic amplification (sPMCA) reactions. Conversely, recPrP^Sc molecules did not accelerate the formation of amyloid in vitro, under conditions that produce recPrP fibers spontaneously. Ultrastructurally, recombinant prions appear to be small spherical aggregates rather than elongated fibers, as determined by atomic force and electron microscopy. Taken together, our results show that recPrP^Sc molecules and PrP fibers have different ultrastructural features and seeding specificities, suggesting that prion infectivity may be propagated by a specific and unique assembly pathway facilitated by cofactors.

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