terça-feira, julho 27, 2010

Spontaneous generation of mammalian prions

Author Affiliations

Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London WC1N 3BG, United Kingdom

↵ ²Present address: Department of Infectology, Scripps Florida, Jupiter, FL 33458.

Edited by David S. Eisenberg, University of California, Los Angeles, CA, and approved June 29, 2010 (received for review March 28, 2010)

Abstract

Prions are transmissible agents that cause lethal neurodegeneration in humans and other mammals. Prions bind avidly to metal surfaces such as steel wires and, when surface-bound, can initiate infection of brain or cultured cells with remarkable efficiency. While investigating the properties of metal-bound prions by using the scrapie cell assay to measure infectivity, we observed, at low frequency, positive assay results in control groups in which metal wires had been coated with uninfected mouse brain homogenate. This phenomenon proved to be reproducible in rigorous and exhaustive control experiments designed to exclude prion contamination. The infectivity generated in cell culture could be readily transferred to mice and had strain characteristics distinct from the mouse-adapted prion strains used in the laboratory. The apparent ”spontaneous generation” of prions from normal brain tissue could result if the metal surface, possibly with bound cofactors, catalyzed de novo formation of prions from normal cellular prion protein. Alternatively, if prions were naturally present in the brain at levels not detectable by conventional methods, metal surfaces might concentrate them to the extent that they become quantifiable by the scrapie cell assay.

cell culture

scrapie

metal

Creutzfeldt-Jakob disease

Footnotes

¹To whom correspondence may be addressed. E-mail:j.collinge@prion.ucl.ac.uk or charlesw@scripps.edu.
Author contributions: J.A.E., J.D.F.W., G.S.J., C.W., and J.C. designed research; J.A.E., N.G., J.A., S.J., J.D.F.W., and J.L. performed research; J.A.E., J.D.F.W., S.B., G.S.J., C.W., and J.C. analyzed data; and J.A.E., C.W., and J.C. wrote the paper.
Conflict of interest statement: J.C. is a director and J.C., J.D.F.W. and G.S.J. are consultants and shareholders of D-Gen, an academic spin-out company in the field of prion disease diagnosis, decontamination, and therapy. D-Gen markets the monoclonal antibody ICSM35 used in this study.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1004036107/-/DCSupplemental.