Journal article
Discovery of a novel, monocationic, small-molecule inhibitor of scrapie prion accumulation in cultured sheep microglia and Rov cells
PloS one, Vol.7(11), pp.e51173-e51173
2012
Handle:
https://hdl.handle.net/2376/110440
PMCID: PMC3511409
PMID: 23226483
Abstract
Prion diseases, including sheep scrapie, are neurodegenerative diseases with the fundamental pathogenesis involving conversion of normal cellular prion protein (PrP(C)) to disease-associated prion protein (PrP(Sc)). Chemical inhibition of prion accumulation is widely investigated, often using rodent-adapted prion cell culture models. Using a PrP(Sc)-specific ELISA we discovered a monocationic phenyl-furan-benzimidazole (DB772), which has previously demonstrated anti-pestiviral activity and represents a chemical category previously untested for anti-prion activity, that inhibited PrP(Sc) accumulation and prion infectivity in primary sheep microglial cell cultures (PRNP 136VV/154RR/171QQ) and Rov9 cultures (VRQ-ovinized RK13 cells). We investigated potential mechanisms of this anti-prion activity by evaluating PrP(C) expression with quantitative RT-PCR and PrP ELISA, comparing the concentration-dependent anti-prion and anti-pestiviral effects of DB772, and determining the selectivity index. Results demonstrate at least an approximate two-log inhibition of PrP(Sc) accumulation in the two cell systems and confirmed that the inhibition of PrP(Sc) accumulation correlates with inhibition of prion infectivity. PRNP transcripts and total PrP protein concentrations within cell lysates were not decreased; thus, decreased PrP(C) expression is not the mechanism of PrP(Sc) inhibition. PrP(Sc) accumulation was multiple logs more resistant than pestivirus to DB772, suggesting that the anti-PrP(Sc) activity was independent of anti-pestivirus activity. The anti-PrP(Sc) selectivity index in cell culture was approximately 4.6 in microglia and 5.5 in Rov9 cells. The results describe a new chemical category that inhibits ovine PrP(Sc) accumulation in primary sheep microglia and Rov9 cells, and can be used for future studies into the treatment and mechanism of prion diseases.
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Details
- Title
- Discovery of a novel, monocationic, small-molecule inhibitor of scrapie prion accumulation in cultured sheep microglia and Rov cells
- Creators
- James B Stanton - Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA. jstanton@vetmed.wsu.eduDavid A SchneiderKelcey D DinkelBethany F BalmerTimothy V BaszlerBruce A MathisonDavid W BoykinArvind Kumar
- Publication Details
- PloS one, Vol.7(11), pp.e51173-e51173
- Academic Unit
- Veterinary Microbiology and Pathology, Department of; Paul G. Allen School for Global Animal Health
- Publisher
- United States
- Grant note
- T32 GM008336 / NIGMS NIH HHS R01 AI064200 / NIAID NIH HHS AI064200 / NIAID NIH HHS
- Identifiers
- 99900547293901842
- Language
- English
- Resource Type
- Journal article