Self-Propagating Mechanism of Prion Diseases

Pron病是一种可传播的神经退行性疾病，由错误折叠和 Pron蛋白的聚集，并显示不同的疾病表型。不管是什么病 表型上，胶质细胞的慢性炎症被认为是疾病发病机制的核心。这个 疾病表型的多样性归因于普恩蛋白或PrPC的正常形式 错误折叠成多个结构不同的、自我复制的PrPSc状态，称为PrPSc菌株或 子类型。不同PrPSc结构如何通过中枢神经系统引起不同的病理反应 人们对此仍然知之甚少。事实上，菌株特异性PrPSc结构与中枢神经系统的关系 回应仍然是经验的，而一种机制将以可预测的方式描述它们的关系 缺乏风度。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该领域的一个关键差距。这个 目前的应用提出了一种新的机制，根据这一机制，N-碳水化合物表位由N- PrPSc表面的连接糖链决定了中枢神经系统的应变特异性反应。这一新的关键要素 机制是PrPSc选择性地招募PrPC糖型，这是由菌株特异性控制的 PrPSc结构，并导致PrPSc表面碳水化合物表位的菌株特异性模式。作为一部分 在这一机制中，我们认为PrPSc的沉积触发了胶质细胞的表型变化，其中 由此产生的胶质表型由PrPSc表面的碳水化合物表位模式决定。为 经过对上述机制的严格测试，我们开发出了操纵PrPSc的生化方法 体外碳水化合物模式，并在动物中产生具有独特糖基化状态的新PrPSc状态。 目标1将测试PrPC糖型是否以菌株特异性的方式选择性地招募到PrPSc中。 目标2将研究PrPSc碳水化合物表位和胶质细胞激活状态之间的关系， 而Aim 3将阐明PrPSc的分子特征，这些分子特征与炎症和 神经退行性变。多学科方法，包括动物病理学、原代细胞培养、质量 光谱和生化技术将被用来阐明慢性阻塞性肺疾病背后的机制 炎症和神经退行性变。这项研究将对新的假设进行严格的检验 PrPSc碳水化合物表位在决定神经胶质细胞功能状态中的作用。当项目完成后， 一幅关于N-连接的多聚糖在普恩病毒疾病中的作用的综合图景将会出现。预计 这项研究将为Pron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.