Abstract
Prion diseases, including sheep scrapie, are neurodegenerative diseases with the fundamental pathogenesis involving conversion of normal cellular prion protein (PrPC) to disease-associated prion protein (PrPSc). Chemical inhibition of prion accumulation is widely investigated, often using rodent-adapted prion cell culture models. Using a PrPSc-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 PrPSc 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 PrPC 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 PrPSc accumulation in the two cell systems and confirmed that the inhibition of PrPSc accumulation correlates with inhibition of prion infectivity. PRNP transcripts and total PrP protein concentrations within cell lysates were not decreased; thus, decreased PrPC expression is not the mechanism of PrPSc inhibition. PrPSc accumulation was multiple logs more resistant than pestivirus to DB772, suggesting that the anti-PrPSc activity was independent of anti-pestivirus activity. The anti-PrPSc 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 PrPSc accumulation in primary sheep microglia and Rov9 cells, and can be used for future studies into the treatment and mechanism of prion diseases.
Highlights
Prion diseases are progressive, fatal, transmissible, neurodegenerative diseases, which include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in deer and elk, and various forms of Creutzfeldt-Jakob disease (CJD) and kuru in humans [1]
Despite previous research investigating compounds with antiPrPSc activity [43,44,45], no effective chemotherapeutics exist for the treatment or prevention of prion diseases
Identification of new classes of anti-prion compounds is vital, for the practical application of in vivo chemotherapeutics, and for investigations studying the mechanisms of PrPSc conversion and accumulation
Summary
Prion diseases (transmissible spongiform encephalopathies [TSEs]) are progressive, fatal, transmissible, neurodegenerative diseases, which include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in deer and elk, and various forms of Creutzfeldt-Jakob disease (CJD) and kuru in humans [1]. The central feature of prion pathogenesis is the conversion of the normal cellular form of the host-encoded prion protein (PrPC [C superscript for cellular]) to an abnormal isoform, designated PrPSc (Sc superscript for sheep scrapie) [4,5,6]. This post-translational conversion involves a conformational change resulting in a detergent-insoluble, partially protease-resistant molecule that aggregates in affected cells and serves as the marker for prion diseases. Continued investigation into new classes of anti-prion compounds is warranted, for the development of effective in vivo anti-prion molecules, and as research tools to elucidate the cellular pathogenesis of prion diseases
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