BIOCHEMISTRY OF SCRAPIE PATHOGENESIS

传染性海绵状脑病(TSE或Prion病)是一种致命的神经退行性疾病，如瘙痒病、克雅氏病(CJD)、疯牛病和慢性衰弱病(CWD)。我们的项目旨在了解和阻止PrP-RES的积累，PrP-RES是PrP蛋白(PrP)的异常形式，似乎是TSE传播和发病的基础。利用细胞培养和无细胞体系，我们1)确定了四吡咯是一类新的PrP-RES形成抑制剂，2)证明了PrP-RES需要一个完整的二硫键才能转化为PrP-RES，3)证明了不同构象的PrP-RES与不同的仓鼠TSE菌株有关，4)分析了已知的PrP-RES形成抑制剂刚果红的结构和功能。5)建立了一种新的无细胞方法来监测PrP-RES与正常PrP之间的结合作用，从而导致后者转化为前者；6)评估了CWD感染的鹿和麋鹿的PrP-RES诱导人、牛和其他物种的正常PrP向PrP-RES转化的能力。--传染性海绵状脑病、普恩病毒、神经退行性变、慢性衰竭性疾病、瘙痒病、克雅氏病

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 thwarting the accumulation of PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. Using cell culture and cell-free systems we have 1) identified tetrapyrroles as a new class of inhibitors of PrP-res formation, 2) demonstrated a need for an intact disulfide bond in PrP for its conversion to PrP-res, 3) demonstrated that different conformations of PrP-res are associated with different TSE strains in hamsters, 4) analyzed the structure-function aspects of Congo red, a known inhibitor of PrP-res formation, 5) developed a new cell-free assay for monitoring the binding interactions between PrP-res and normal PrP that lead to conversion of the latter into the former and 6) assessed the ability of PrP-res from CWD-infected deer and elk to induce the conversion of normal PrP from humans, cattle and other species to PrP-res. - Transmissible spongiform encephalopathies, prions, neurodegeneration, chronic wasting disease, scrapie, Creutzfeldt-Jakob disease