Transmissible spongiform encephalopathies (TSEs or prion disease) are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). Our project is aimed at understanding and blocking the conversion of normal PrP (PrP-sen) to PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. We have employed a wide variety of cell biological, biochemical, biophysical and in vivo experimental approaches. Over the last year we have 1) developed a high throughput scrapie-infected neuroblastoma cell based screen for inhibitors of PrP-res formation, 2) screened >2000 compounds (natural products or drugs approved for other purposes) and identified ~258 new inhibitors, 17 of which are highly potent against 2 different scrapie strains, 3) begun testing these and other inhibitors for prophylactic and therapeutic activities against scrapie in animals, 4) determined that several inhibitors of PrP-res formation can induce conformational changes, aggregation and fibril formation in recombinant PrP-sen, 5) developed a new type of scrapie-infected neuronal cell line (SN56), 6) obtained initial evidence that laminin binding to normal PrP impedes its conversion to PrP-res, 7) identified a strain-specific and metal-ion dependent folding domain of PrP-res, 8) isolated the minimal oligomeric units of PrP-res between 100-300 kD that retain the protease-resistant and conversion-inducing properties of PrP-res and 8) transmitted and adapted chronic wasting disease from deer and elk to hamsters and transgenic mice expressing hamster PrP-sen.
| 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 |
| 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 |
| 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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