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.
Laboratory of Persistent Viral Diseases and 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
http://www.nature.com/nature/journal/v437/n7056/abs/nature03989.html
Editor's Summary
8 September 2005
Prions: form and infectivity
The prospects of limiting the spread of transmissible spongiform
encephalopathies such as Creutzfeldt-Jakob disease depend in part on
identifying the most infectious forms of the prions that carry the diseases.
A study of modified scrapie prions shows that clusters of 14 to 28 prion
proteins are the most infectious and that clusters of less than six
molecules have virtually no infectivity. That could have implications for
the treatment of diseases such as Alzheimer's and Parkinson's, characterized
by deposition of prion-related amyloid fibrils. It's possible that efforts
to alleviate symptoms by destabilizing these large protein aggregates might
make things worse by producing smaller, more infective particles.
Andrew D. Miranker
doi: 10.1038/nature03989