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Published online on May 29, 2007, 10.1073/pnas.0702662104
PNAS | June 5, 2007 | vol. 104 | no. 23 | 9741-9746


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From the Cover
BIOLOGICAL SCIENCES / GENETICS
Formation of native prions from minimal components in vitro

Nathan R. Deleault*, Brent T. Harris{dagger}, Judy R. Rees{ddagger}, and Surachai Supattapone*,§,¶

Departments of *Biochemistry, {dagger}Pathology, {ddagger}Community and Family Medicine (Biostatistics and Epidemiology), and §Medicine, Dartmouth Medical School, Hanover, NH 03755

Edited by Reed B. Wickner, National Institutes of Health, Bethesda, MD, and approved April 26, 2007 (received for review March 24, 2007)

The conformational change of a host protein, PrPC, into a disease-associated isoform, PrPSc, appears to play a critical role in the pathogenesis of prion diseases such as Creutzfeldt–Jakob disease and scrapie. However, the fundamental mechanism by which infectious prions are produced in neurons remains unknown. To investigate the mechanism of prion formation biochemically, we conducted a series of experiments using the protein misfolding cyclic amplification (PMCA) technique with a preparation containing only native PrPC and copurified lipid molecules. These experiments showed that successful PMCA propagation of PrPSc molecules in a purified system requires accessory polyanion molecules. In addition, we found that PrPSc molecules could be formed de novo from these defined components in the absence of preexisting prions. Inoculation of samples containing either prion-seeded or spontaneously generated PrPSc molecules into hamsters caused scrapie, which was transmissible on second passage. These results show that prions able to infect wild-type hamsters can be formed from a minimal set of components including native PrPC molecules, copurified lipid molecules, and a synthetic polyanion.

polyanion | PrP | purified | spontaneous | de novo

Author contributions: N.R.D. and S.S. designed research; N.R.D., B.T.H., and S.S. performed research; N.R.D., B.T.H., J.R.R., and S.S. analyzed data; and N.R.D., B.T.H., J.R.R., and S.S. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

See Commentary on page 9551.

This article contains supporting information online at www.pnas.org/cgi/content/full/0702662104/DC1.

To whom correspondence should be addressed at: Department of Biochemistry, 7200 Vail Building, Dartmouth Medical School, Hanover, NH 03755. E-mail: supattapone{at}dartmouth.edu

© 2007 by The National Academy of Sciences of the USA


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