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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.


  1. Caughey, B. & Lansbury, P. T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003)

    Article  CAS  Google Scholar 

  2. Kayed, R. et al. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J. Biol. Chem. 279, 46363–46366 (2004)

    Article  CAS  Google Scholar 

  3. Kocisko, D. A. et al. Cell-free formation of protease-resistant prion protein. Nature 370, 471–474 (1994)

    Article  ADS  CAS  Google Scholar 

  4. Prusiner, S. B. Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998)

    Article  ADS  CAS  Google Scholar 

  5. Silveira, J. R., Caughey, B. & Baron, G. S. Prion protein and the molecular features of transmissible spongiform encephalopathy agents. Curr. Top. Microbiol. Immunol. 284, 1–50 (2004)

    CAS  PubMed  Google Scholar 

  6. Caughey, B., Raymond, G. J., Kocisko, D. A. & Lansbury, P. T. Jr Scrapie infectivity correlates with converting activity, protease resistance, and aggregation of scrapie-associated prion protein in guanidine denaturation studies. J. Virol. 71, 4107–4110 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Prusiner, S. B. Molecular biology of prion diseases. Science 252, 1515–1522 (1991)

    Article  ADS  CAS  Google Scholar 

  8. Brown, P., Liberski, P. P., Wolff, A. & Gajdusek, D. C. Conservation of infectivity in purified fibrillary extracts of scrapie-infected hamster brain after sequential enzymatic digestion or polyacrylamide gel electrophoresis. Proc. Natl Acad. Sci. USA 87, 7240–7244 (1990)

    Article  ADS  CAS  Google Scholar 

  9. Safar, J. et al. Molecular mass, biochemical composition, and physicochemical behaviour of the infectious form of the scrapie precursor protein monomer. Proc. Natl Acad. Sci. USA 87, 6373–6377 (1990)

    Article  ADS  CAS  Google Scholar 

  10. Hope, J. The nature of the scrapie agent: the evolution of the virino. Ann. NY Acad. Sci. 724, 282–289 (1994)

    Article  ADS  CAS  Google Scholar 

  11. Morillas, M., Vanik, D. L. & Surewicz, W. K. On the mechanism of α-helix to β-sheet transition in the recombinant prion protein. Biochemistry 40, 6982–6987 (2001)

    Article  CAS  Google Scholar 

  12. Alper, T., Haig, D. A. & Clarke, M. C. The exceptionally small size of the scrapie agent. Biochem. Biophys. Res. Commun. 22, 278–284 (1966)

    Article  CAS  Google Scholar 

  13. Gibbs, C. J. Jr, Gajdusek, D. C. & Latarjet, R. Unusual resistance to ionizing radiation of the viruses of kuru, Creutzfeldt-Jakob disease, and scrapie. Proc. Natl Acad. Sci. USA 75, 6268–6270 (1978)

    Article  ADS  Google Scholar 

  14. Bellinger-Kawahara, C. G., Kempner, E., Groth, D., Gabizon, R. & Prusiner, S. B. Scrapie prion liposomes and rods exhibit target sizes of 55,000 Da. Virology 164, 537–541 (1988)

    Article  CAS  Google Scholar 

  15. Gabizon, R., McKinley, M. P. & Prusiner, S. B. Purified prion proteins and scrapie infectivity copartition into liposomes. Proc. Natl Acad. Sci. USA 84, 4017–4021 (1987)

    Article  ADS  CAS  Google Scholar 

  16. Raymond, G. J. et al. Molecular assessment of the potential transmissibilities of BSE and scrapie to humans. Nature 388, 285–288 (1997)

    Article  ADS  CAS  Google Scholar 

  17. Prusiner, S. B. et al. Molecular properties, partial purification, and assay by incubation period measurements of the hamster scrapie agent. Biochemistry 19, 4883–4891 (1980)

    Article  CAS  Google Scholar 

  18. Gast, K., et al. in Laser Light Scattering in Biochemistry (eds Harding, S. E., Sattelle, D. B. & Bloomfield, V. A.) 209–224 (The Royal Society of Chemistry, Cambridge, 1992)

    Google Scholar 

  19. Masel, J., Jansen, V. A. & Nowak, M. A. Quantifying the kinetic parameters of prion replication. Biophys. Chem. 77, 139–152 (1999)

    Article  CAS  Google Scholar 

  20. Masel, J., Genoud, N. & Aguzzi, A. Efficient inhibition of prion replication by PrP-Fc2 suggests that the prion is a PrPSc oligomer. J. Mol. Biol. 345, 1243–1251 (2005)

    Article  CAS  Google Scholar 

  21. Tzaban, S. et al. Protease-sensitive scrapie prion protein in aggregates of heterogeneous sizes. Biochemistry 41, 12868–12875 (2002)

    Article  CAS  Google Scholar 

  22. Riesner, D. et al. Disruption of prion rods generates 10-nm spherical particles having high α-helical content and lacking scrapie infectivity. J. Virol. 70, 1714–1722 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jeffrey, M. et al. Correlative light and electron microscopy studies of PrP localisation in 87V scrapie. Brain Res. 656, 329–343 (1994)

    Article  CAS  Google Scholar 

  24. Raymond, G. J. & Chabry, J. in Techniques in Prion Research (eds Lehmann, S. & Grassi, J.) 16–26 (Birkhauser, Basel, 2004)

    Book  Google Scholar 

  25. Wahlund, K.-G. in Field-Flow Fractionation Handbook (eds Schimpf, M., Caldwell, K. & Giddings, J. C.) 279–294 (John Wiley & Sons, New York, 2000)

    Google Scholar 

  26. Kocisko, D. A. et al. New inhibitors of scrapie-associated prion protein formation in a library of 2000 drugs and natural products. J. Virol. 77, 10288–10294 (2003)

    Article  CAS  Google Scholar 

  27. Maxson, L., Wong, C., Herrmann, L. M., Caughey, B. & Baron, G. S. A solid-phase assay for identification of modulators of prion protein interactions. Anal. Biochem. 323, 54–64 (2003)

    Article  CAS  Google Scholar 

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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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