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、牛的牛海绵状脑病（bovine spongiform encephalopathies，BSE）以及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强调了了解TSE发病机制和开发有效的抗TSE治疗方法的重要性。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）确定不同的PrP-sen二级结构如何参与PrP-res的形成，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）确定TSE菌株的分子基础。在分子水平上，我们已经表明，影响物种特异性PrP-res形成的氨基酸在物种之间存在差异。我们还证明了PrP-sen中不同的二级结构通过改变PrP-sen加工和/或折叠来影响PrP-res的形成。使用我们已经开发的组织培养系统，我们已经开始解剖TSE株特异性差异的PrP-res形成和感染的敏感性。作为这些研究的结果，我们发现非神经元细胞类型可能对TSE感染敏感。在治疗方法方面，我们已经发现，环状四吡咯酞菁四磺酸酯可以在TSE疾病的鼠模型中特异性地用于延迟疾病发作。

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) in cattle 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 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) determing how different PrP-sen secondary structures are involved in PrP-res formation, 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) determining the molecular basis of TSE strains. At the molecular level, we have shown that the amino acids that influence species-specific PrP-res formation differ between species. We have also demonstrated that different secondary structures in PrP-sen influence PrP-res formation by altering PrP-sen processing and/or folding. Using a tissue culture system we have developed, we have begun to dissect TSE strain-specific differences in both PrP-res formation and susceptibility to infection. As a result of these studies, we have found that non-neuronal cell types can be susceptible to TSE infection. In terms of therapeutic approaches, we have found that the cyclic tetrapyrolle phthalocyanine tetrasulfonate can be used prophylactically to delay disease onset in a murine model of TSE disease.