Molecular Genetics Of Scrapie Pathogenesis

传染性海绵状脑病（Transmissible spongiform encephalopathies，TSE）是一组罕见的神经退行性疾病，包括人类的克雅氏病（Creutzfeldt-Jakob disease，CJD）、绵羊的痒病、牛海绵状脑病（bovine spongiform encephalopathies，BSE）和骡鹿和麋鹿的慢性消耗病（chronic wasting disease，CWD）。TSE传染性可跨越物种屏障。BSE在英国感染人类的事实以及对CWD在美国可能具有类似作用的担忧强调了了解TSE发病机制和开发有效抗TSE疗法的重要性。TSE疾病的感染因子的确切性质尚不清楚。正常宿主蛋白（PrP-sen）和该蛋白的异常蛋白酶K抗性形式PrP-res之间的氨基酸同源性可影响对感染的易感性。PrP-res的形成与感染性密切相关，并且PrP-res已被假设为TSE疾病中的感染因子。了解这种蛋白质是如何产生的，对于我们理解TSE发病机制和设计治疗策略以防止其合成至关重要。我的研究在分子和致病水平上解决了TSE疾病的许多不同方面。特别是，我的实验室专注于：1）确定TSE菌株的分子基础，2）精确定义PrP-res形成发生的不同细胞区室，3）开发有效的治疗TSE药物，4）确定TSE感染期间发生的最早事件，5）研究PrP-res物种特异性形成中涉及的PrP区域。 在过去的一年中，我们已经证明，PrP中的氨基酸残基是重要的跨物种形成的PrP-res不同的物种。我们还表明，化合物酞菁四磺酸盐可以对TSE感染起预防和治疗作用，并且可以完全消除溶液中的TSE感染性。最后，我们已经证明了非神经元细胞对TSE感染完全敏感，并且细胞对感染的易感性不能基于PrP-sen表达水平来预测。

Transmissible spongiform encephalopathies (TSE) are a group of rare neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in mule deer and elk. TSE infectivity can cross species barriers. The fact that BSE has infected humans in Great Britain and concerns that CWD may act similarly in the US underscores the importance of understanding TSE pathogenesis and developing effective anti-TSE therapeutics. The precise nature of the infectious agent of the TSE diseases is unknown. Susceptibility to infection can be influenced by amino acid homology between a normal host protein (PrP-sen) and the abnormal proteinase K-resistant form of this protein, PrP-res. Formation of PrP-res is closely associated with infectivity and PrP-res has been hypothesized to be the infectious agent in the TSE diseases. An understanding of how this protein is made is critical for our understanding of TSE pathogenesis and for devising therapeutic strategies to prevent its synthesis. My studies address many different aspects of the TSE diseases at both the molecular and pathogenic level. In particular, my laboratory focuses on: 1) determining the molecular basis of TSE strains, 2) precisely defining the different cellular compartments where PrP-res formation occurs, 3) development of effective therapeutic TSE agents, 4) identifying the earliest events which occur during TSE infection, and 5) studying the regions of PrP involved in the species-specific formation of PrP-res. In the last year, we have demonstrated that the amino acid residues in PrP that are important in cross-species formation of PrP-res vary depending upon the species. We have also shown that the compound phthalocyanine tetrasulfonate can act prophylactically and therapeutically against TSE infection and can completely inactivate TSE infectivity in solution. Finally, we have demonstrated that non-neuronal cells are fully susceptible to TSE infection and that the susceptibility of cells to infection can not be predicted based upon PrP-sen expression levels.