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The most infectious prion protein particles


Neurodegenerative diseases such as Alzheimer's, Parkinson's and the transmissible spongiform encephalopathies (TSEs) are characterized by abnormal protein deposits, often with large amyloid fibrils. However, questions have arisen as to whether such fibrils or smaller subfibrillar oligomers are the prime causes of disease1,2. Abnormal deposits in TSEs are rich in PrPres, a protease-resistant form of the PrP protein with the ability to convert the normal, protease-sensitive form of the protein (PrPsen) into PrPres (ref. 3). TSEs can be transmitted between organisms by an enigmatic agent (prion) that contains PrPres (refs 4 and 5). To evaluate systematically the relationship between infectivity, converting activity and the size of various PrPres-containing aggregates, PrPres was partially disaggregated, fractionated by size and analysed by light scattering and non-denaturing gel electrophoresis. Our analyses revealed that with respect to PrP content, infectivity and converting activity peaked markedly in 17–27-nm (300–600 kDa) particles, whereas these activities were substantially lower in large fibrils and virtually absent in oligomers of ≤5 PrP molecules. These results suggest that non-fibrillar particles, with masses equivalent to 14–28 PrP molecules, are the most efficient initiators of TSE disease.

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Figure 1: Analysis of fractionated PrPres.
Figure 2: PAGE analyses of detergent-treated PrPres.
Figure 3: Transmission electron microscopy analyses of fractionated PrPres.


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We thank C. Y. Huang and D. Follmann (Biostatistics Research Branch, NIH/NIAID) for performing statistical analyses. We thank B. Chesebro, G. S. Baron and S. J. Robertson for critiquing the manuscript. This research was supported in part by the Intramural Research Program of the NIH/NIAID. V.L.S. acknowledges support from the Alberta Heritage Foundation for Medical Research through a clinical fellowship award. Author Contributions J.R.S. spearheaded the project, developed the critical methods and performed the PrPres disaggregation, fractionation and particle analyses. G.J.R. and A.G.H. purified PrPres and performed bioassays and other supporting experiments. R.E.R. provided bioassay standard curve data. V.L.S. and S.F.H. performed electron microscopy. B.C. helped with project design, data interpretation and writing (primarily with J.R.S.)

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Correspondence to Byron Caughey.

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Supplementary Notes

This file contains Supplementary Methods, Supplementary Discussion, additional references, and six Supplementary Figures. The file provides information about the selection of detergent conditions used in the study, details on the statistical analyses used to determine error bars, and additional data to support the conclusions derived from the figures in the main text. (DOC 1670 kb)

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Silveira, J., Raymond, G., Hughson, A. et al. The most infectious prion protein particles. Nature 437, 257–261 (2005).

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