Transmissible spongiform encephalopathies (TSEs or prion disease) are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), BSE and chronic wasting disease (CWD). Our project is aimed at understanding and blocking the accumulation of PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. Using animal models, cell culture and cell-free systems we have 1) identified the curry spice curcumin as a potent and edible new inhibitor of PrP-res formation, 2) compared the in vivo anti-scrapie effects of deuteroporphyrins containing different divalent metal ions, 3) determined that reshuffling of the disulfide bonds in PrP-res is not necessary for PrP-res formation, 4) established cellular models of acute scrapie infection and PrP-res formation using scrapie brain microsomes as sources of infectivity, 5) determined that normal PrP and PrP-res do not interact efficiently unless they are in the same membrane, 6) analyzed the role of helix 1 salt bridges in PrP-res formation, 7) developed solid phase conversion assays in an effort to develop high-throughput screens for potential anti-TSE drugs, 8) further characterized regions of PrP-res that are differently folded as a function of TSE strain, and 9) begun to assess the role of PrP in the heart by looking for differences in resistance of wild-type and PrP knockout mice to ischemia-reperfusion injury.
| Sim, Valerie L; Caughey, Byron (2008) Ultrastructures and strain comparison of under-glycosylated scrapie prion fibrils. Neurobiol Aging : |
| Atarashi, Ryuichiro; Wilham, Jason M; Christensen, Leah et al. (2008) Simplified ultrasensitive prion detection by recombinant PrP conversion with shaking. Nat Methods 5:211-2 |
| Liberski, Pawel P; Brown, David R; Sikorska, Beata et al. (2008) Cell death and autophagy in prion diseases (transmissible spongiform encephalopathies). Folia Neuropathol 46:1-25 |
| Caughey, Byron; Baron, Gerald S (2008) Are cheetahs on the run from prion-like amyloidosis? Proc Natl Acad Sci U S A 105:7113-4 |
| Atarashi, Ryuichiro; Moore, Roger A; Sim, Valerie L et al. (2007) Ultrasensitive detection of scrapie prion protein using seeded conversion of recombinant prion protein. Nat Methods 4:645-50 |
| Caughey, Winslow S; Priola, Suzette A; Kocisko, David A et al. (2007) Cyclic tetrapyrrole sulfonation, metals, and oligomerization in antiprion activity. Antimicrob Agents Chemother 51:3887-94 |
| Lee, Kil Sun; Caughey, Byron (2007) A simplified recipe for prions. Proc Natl Acad Sci U S A 104:9551-2 |
| Kocisko, David A; Bertholet, Nadine; Moore, Roger A et al. (2007) Identification of prion inhibitors by a fluorescence-polarization-based competitive binding assay. Anal Biochem 363:154-6 |
| Lee, Kil S; Raymond, Lynne D; Schoen, Brianna et al. (2007) Hemin interactions and alterations of the subcellular localization of prion protein. J Biol Chem 282:36525-33 |
| Raymond, Gregory J; Raymond, Lynne D; Meade-White, Kimberly D et al. (2007) Transmission and adaptation of chronic wasting disease to hamsters and transgenic mice: evidence for strains. J Virol 81:4305-14 |
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