Laboratory of Persistent Viral Diseases

Byron Caughey, Ph.D.

Chief, TSE/Prion Biochemistry Section
Senior Investigator

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 TSEs such as scrapie, bovine spongiform encephalopathy (BSE) or 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.

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, Brad Groveman, Allison Kraus, Christina Orrù, Leah Christensen, Sarah Vascellari, Jason Wilham, Kelly Barton, Greg Raymond, Byron Caughey, Lynne Raymond

Selected Publications

Orrú CD, Wilham JM, Raymond LD, Kuhn F, Schroeder B, Raeber AJ, Caughey B. Prion disease blood test using immunoprecipitation and improved quaking-induced conversion. mBio. 2011. 2:e00078-11.

Baron GS, Hughson AG, Raymond GJ, Offerdahl DK, Barton KA, Raymond LD, Dorward DW, Caughey B. Effect of glycans and GPI anchor on strain dependent conformations of scrapie prion protein: improved purifications and IR spectra. Biochem. 2011. 50:4479-90.

Smirnovas V, Baron GS, Offerdahl DK, Raymond GJ, Caughey B, Surewicz W. Structural organization of brain-derived mammalian prions as probed by hydrogen exchange. Nature Struct & Mol Biol. 2011. 18:504-6.

Wilham JM, Orrú CD, Bessen RA, Atarashi R, Sano K, Race B, Meade-White KD, Taubner LM, Timmes A, Caughey B. Rapid end-point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Pathogens. 2010. 6:e1001217.

Kim J-I, Cali I, Surewicz K, Kong Q, Raymond GJ, Atarashi R, Race B, Qing L, Gambetti P, Caughey B, Surewicz WK. Mammalian prions generated from bacterially expressed prion protein in the absence of any mammalian cofactors. J Biol Chem. 2010. 285(19):14083-7.

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. 2010. 395:475-90.

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