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是一种异常形式的朊病毒蛋白（PrP），似乎是TSE传播和发病的基础。通过细胞培养和无细胞系统，我们已经1)鉴定了溶酶性胺、半胱氨酸蛋白酶抑制剂和某些新的PrP肽片段作为潜在的治疗性PrP-res形成的新抑制剂，2)描述了PrP-res形成过程中发生的相互作用位点，3)描述了来自不同物种的正常PrP和PrP-res分子之间的相互作用，这些相互作用可能控制tse的种间传播。4)确定了正常PrP的膜附着对其转化为PrP-res的影响，5)分析了PrP-res形成的可逆性，6)鉴定了硫酸肝素和血清淀粉样蛋白P成分是PrP-res形成的刺激物，6)评估了ccd感染鹿和麋鹿的PrP-res诱导人正常PrP转化的能力。研究表明，洗涤剂可以诱导正常PrP的构象变化和原纤维的形成，这与PrP-res的形成相似。

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 lysosomotropic amines, cysteine protease inhibitors and certain new PrP peptide fragments as potentially therapeutic new inhibitors of PrP-res formation, 2) described sites of interaction that occur during PrP-res formation, 3) described interactions between normal PrP and PrP-res molecules from different species that may control interspecies transmissibilities of TSEs, 4) determined effects of the membrane attachment of normal PrP on its conversion to PrP-res, 5) assayed the reversibility of PrP-res formation, 6)identified heparan sulfate and serum amyloid P component as stimulators of PrP-res formation, 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 and 7) showed that a detergent can induce conformational changes and fibril formation in normal PrP that are reminiscent of PrP-res formation.