Laboratory of Persistent Viral Diseases

Byron Caughey, Ph.D.

Chief, TSE/Prion Biochemistry Section
Senior Investigator

Atomic force micrograph of infectious prion fibrils. Credit: Dr Valerie Sim

TSE/Prion Biochemistry Section

Dr. Caughey received his Ph.D. in biochemistry from the University of Wisconsin-Madison in 1985 and completed postdoctoral studies in pharmacology at Duke University Medical Center in 1985 – 1986. He has conducted transmissible spongiform encephalopathies (TSE)/prion research in the Laboratory of Persistent Viral Diseases (LPVD) since 1986. Dr. Caughey is also an editor for the Journal of Virology.

NMR-based structure of prion protein octapeptide repeats when bound to a sulfated glycan inhibitor (not shown). Credit: Dr Lara Taubner

Description of Research Program

Prion diseases or transmissible spongiform encephalopathies (TSEs) such as scrapie, BSE (mad cow disease), Creutzfeldt-Jakob disease, and chronic wasting disease are infectious neurodegenerative protein misfolding diseases. We emphasize biochemical, biophysical, and cell biological studies of the function of prion protein and its conversion to pathological forms. The structure of the fundamental infectious particles (prions) are being characterized using approaches including infrared spectroscopy, circular dichroism spectroscopy, mass spectrometry, field-flow fractionation, light scattering, atomic force microscopy, and electron microscopy. Fluorescence microscopy techniques are being used to visualize the process by which prions infect and spread within neural cells in vitro and in vivo.

Fluorescently tagged prions taken up and transported along neuritic projections in a cultured neuron. Credit: Dr Kil Sun Lee

We have developed new cell-free prion protein conversion reactions that serve as rapid ultra-sensitive prion assays and tools for learning about prion structure. Inhibitors of prion protein conversion are being identified and tested as anti-TSE drugs. We are characterizing the interactions of these inhibitors with prion protein using techniques such as nuclear magnetic resonance spectroscopy and fluorescence correlation spectroscopy. This drug-screening effort is aided by our development of new cell culture models of TSE diseases. Finally, we are studying natural analogs of prion protein conversion inhibitors as potential physiological ligands which could play important roles in the normal and pathological functions of prion protein.

Video Explaining Dr. Caughey's Research on Developing a Better Test for the Proteins Responsible for Mad Cow Disease

(Windows Media Player Format, SMIL captioned, 3 MB)
Credit: ScienCentral, Inc.
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Research Group Members

Left to right: Andy Hughson, Leah Christensen, Lara Taubner, Jason Wilham, Kelly Barton, Christina Orrú, Byron Caughey, Lynne Raymond, Greg Raymond, Rie Hasebe (not shown)

Selected Publications

(View list in PubMed.)

Caughey B, Baron GS, Chesebro B, Jeffrey M. Getting a grip on prions: oligomers, amyloids and pathological membrane interactions. Ann Rev Biochem 2009 78:177-204 , Review.

Taubner LM, Bienkiewicz EA, Copié V, Caughey B. Structure of the flexible amino terminal domain of prion protein bound to a sulfated glycan. J Mol Biol 2009, in press

Smirnovas V, Kim J-I, Lu X, Atarashi R, Caughey B and Surewicz WK. Distinct structures of scrapie prion protein (PrPSc)-seeded versus spontaneous recombinant prion protein fibrils revealed by H/D exchange. J Biol Chem 2009 284:24233-41

Sim V, Caughey B, Ultrastructures and strain comparison of under-glycosylated scrapie prion fibrils. Neurobiol Aging 2009 30:2031-2042

Atarashi R, Wilham JM, Christensen L, Hughson AG, Moore RA, Johnson LM, Onwubiko HA, Priola SA, Caughey B. Simplified ultrasensitive prion detection by recombinant PrP conversion with shaking. Nat Methods 2008 3:2011-2012.

Lee KS, Raymond LD, Schoen B, Raymond GJ, Kett L, Moore RA, Johnson LM, Taubner L, Speare JO, Onwubiko HA, Baron GS, Caughey WS, Caughey B. Hemin interactions and alterations of the subcellular localization of prion protein. J Biol Chem 2007 282:36525-33.

Atarashi R, Moore RA, Sim VL, Hughson AG, Dorward DW, Onwubiko HA, Priola SA, Caughey B. Ultrasensitive detection of scrapie prion protein using seeded conversion of recombinant prion protein. Nat Methods 2007 4:645-50.

Caughey B, Baron GS. Prions and their partners in crime. Nature 2006 443:803-10. Review.

Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL, Hayes SF, Caughey B. The most infectious prion protein particles. Nature. 2005 437:257-61.

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