Letter

Nature 437, 257-261 (8 September 2005) | doi: 10.1038/nature03989

The most infectious prion protein particles

Jay R. Silveira1, Gregory J. Raymond1, Andrew G. Hughson1, Richard E. Race1, Valerie L. Sim1, Stanley F. Hayes2 and Byron Caughey1

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.

  1. Laboratory of Persistent Viral Diseases and
  2. Electron Microscopy Core Facility, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA

Correspondence to: Byron Caughey1 Correspondence and requests for materials should be addressed to B.C. (Email: bcaughey@nih.gov).

Received 15 May 2005; Accepted 24 June 2005

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