Self-Propagating Mechanism of Prion Diseases

朊病毒疾病是由错误折叠引起的传染性神经退行性疾病， 朊病毒蛋白的聚集并显示不同的疾病表型。不管是什么病 由于神经胶质细胞的表型，神经胶质细胞的慢性炎症被认为是疾病发病机制的核心。的 疾病表型的多样性归因于朊病毒蛋白或PrPC的正常形式的能力， 错误折叠成多个结构不同的自我复制PrPSc状态，称为朊病毒株，或 亚型不同的PrPSc结构如何通过CNS引起不同的病理反应的问题 仍然知之甚少。事实上，菌株特异性PrPSc结构与CNS之间的关系 反应仍然是经验性的，而一个机制，将描述他们的关系，在一个可预测的 方式缺乏。此外，目前还不清楚PrPSc的分子特征是什么， 慢性炎症和神经变性。缺乏这方面的知识是这一领域的一个主要差距。的 本申请提出了一种新的机制，根据该机制，由N- PrPSc表面上的连接的聚糖决定CNS的菌株特异性反应。这个新的关键因素 PrPSc对PrPC糖型的选择性募集机制是由菌株特异性的 PrPSc的结构和结果在菌株特异性模式的碳水化合物表位上的PrPSc表面。一部分 基于这一机制，我们认为PrPSc的沉积触发了神经胶质细胞的表型变化， 所得到的神经胶质表型由PrPSc表面上的碳水化合物表位的模式决定。为 通过对上述机制的严格测试，我们开发了操纵PrPSc的生物化学方法 在体外的碳水化合物模式，并产生了新的PrPSc国家与独特的糖基化状态的动物。 目的1将测试PrPC糖型是否选择性地和以菌株特异性方式募集到PrPSc中。 目的2将研究PrPSc糖表位与胶质细胞活化状态之间的关系， 而目标3将阐明负责炎症的PrPSc的分子特征， 神经变性多学科方法，包括动物病理学，原代细胞培养， 光谱和生物化学技术，将用于阐明慢性 炎症和神经变性。这项研究将提供一个严格的测试的新假设， PrPSc糖表位在决定神经胶质功能状态中的作用。当项目完成后， N-连接的聚糖在朊病毒疾病中的作用的全面描述将会出现。预计各国 这项研究将为朊病毒疾病的治疗干预提供新的靶点。

Prion diseases are transmissible neurodegenerative maladies that are caused by misfolding and aggregation of the prion protein and display diverse disease phenotypes. Regardless of a disease phenotype, chronic inflammation of the glia is considered to be central to disease pathogenesis. The diversity of disease phenotypes is attributed to the ability of normal form of the prion protein or PrPC to misfold into multiple, structurally distinct, self-replicating PrPSc states referred to as prion strains or subtypes. The question of how different PrPSc structures elicit diverse pathological response by CNS remains poorly understood. In fact, the relationship between strain-specific PrPSc structures and CNS responses remains empirical, whereas a mechanism that would describe their relationship in a predictable manner is lacking. Moreover, it remains unclear what molecular features of PrPSc are responsible for chronic inflammation and neurodegeneration. Lack of this knowledge represents a key gap in the field. The current application proposes a novel mechanism, according to which carbohydrate epitopes formed by N- linked glycans on PrPSc surface determine strain-specific response of CNS. The key element of this new mechanism is a selective recruitment of PrPC glycoforms by PrPSc, which is governed by strain-specific PrPSc structures and results in strain-specific patterns of carbohydrate epitopes on PrPSc surface. As a part of this mechanism, we propose that deposition of PrPSc triggers phenotypic changes in glia, where the resulting glial phenotypes are determined by the patterns of carbohydrate epitopes on PrPSc surface. For rigorous testing of above mechanism, we developed biochemical approaches for manipulating PrPSc carbohydrate patterns in vitro, and generated new PrPSc states with unique glycosylation status in animals. Aim 1 will test whether PrPC glycoforms are recruited into PrPSc selectively and in a strain-specific manner. Aim 2 will examine a relationship between PrPSc carbohydrate epitopes and activation states of glia, whereas Aim 3 will elucidate molecular features of PrPSc responsible for inflammation and neurodegeneration. Multidisciplinary approaches, including animal pathology, primary cell cultures, mass spectrometry and biochemical techniques, will be employed to elucidate the mechanisms behind chronic inflammation and neurodegeneration. This study will provide a rigorous test of the new hypothesis on the role of PrPSc carbohydrate epitopes in determining functional states of glia. When the project is completed, a comprehensive picture of the role of N-linked glycans in prion diseases will emerge. It is anticipated that this study will lead to new targets for therapeutic intervention against prion diseases.