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）鉴定了亲溶酶体胺、半胱氨酸蛋白酶抑制剂和某些新的PrP肽片段作为PrP-res形成的潜在治疗性新抑制剂，2）描述了在PrP-res形成期间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，其可以控制TSE的种间传播，4）确定正常PrP的膜附着对其转化为PrP-res的影响，5）测定PrP-res形成的可逆性，6）鉴定硫酸乙酰肝素和血清淀粉样蛋白P组分作为PrP-res形成的刺激物，6）评估来自CWD感染的鹿和麋鹿的PrP-res诱导来自人的正常PrP转化的能力，牛和其他物种对PrP-res的反应，和7）表明去污剂可以诱导正常PrP中的构象变化和原纤维形成，这使人联想到PrP-res的形成。

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.