BIOCHEMISTRY OF SCRAPIE PATHOGENESIS

传染性海绵状脑病（TSE或朊病毒病）是致命的神经退行性疾病，如羊瘙痒病、克雅氏病（CJD）、疯牛病和慢性消耗性疾病（CWD）。我们的项目旨在了解和阻止PrP-res的积累，PrP-res是朊病毒蛋白（PrP）的异常形式，似乎是TSE传播和发病机制的基础。使用细胞培养和无细胞系统，我们已经1）鉴定了四吡咯作为一类新的PrP-res形成抑制剂，2）证明了PrP中需要完整的二硫键才能转化为PrP-res，3）证明了PrP-res的不同构象与仓鼠中不同的TSE菌株相关，4）分析了刚果红的结构-功能方面，一种已知的PrP-res形成抑制剂，5）开发了一种新的无细胞测定法，用于监测PrP-res和正常PrP之间的结合相互作用，所述结合相互作用导致后者转化为前者，和6）评估了来自感染CWD的鹿和麋鹿的PrP-res诱导来自人的正常PrP转化的能力，牛和其他物种的PrP-res. -传染性海绵状脑病、朊病毒、神经变性、慢性消耗性疾病、羊瘙痒病、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