Project 2: Structural studies of prions

摘要：项目2末梢 许多神经退行性疾病与淀粉样蛋白沉积有关，淀粉样蛋白是错误折叠的蛋白质的聚集体。 具有大致垂直于长的、未分枝的细丝的轴线延伸的特征。示例 包括与多肽有关的阿尔茨海默氏症，与多肽有关的帕金森病 蛋白α-突触核蛋白，包括阿尔茨海默氏症和慢性创伤性脑病在内的许多疾病与 蛋白tau，和CreuzFeldt-Jakob以及其他与哺乳动物PrP蛋白有关的蛋白。 这些疾病的共同特点是异常多肽折叠的自我繁殖，就像最初的那样。 在哺乳动物中识别的PrP来源的Prion。它的结构和自传播特性 PrP的淀粉样蛋白与其他病理性淀粉样蛋白是相同的，这些疾病基本上都是PrP 疾病。因此，分子结构和结构转变是理解这些疾病的关键，并且 最终到设计诊断和治疗干预措施。 对淀粉样蛋白结构的了解将提供有关前体低聚物的信息，这些低聚体在许多情况下 3例被鉴定为有毒物种，并与原纤维具有相同的结构特征。了解以下内容 结合低聚体信息的淀粉样蛋白结构(项目3、4)也将增加 了解包括有毒物种在内的相互转化途径。 这个项目的总体目标是确定与某些最常见的淀粉样蛋白相关的结构 毁灭性的神经退行性疾病。淀粉样蛋白不利于结晶学或溶液核磁共振 因此，主要的研究方法是纤维衍射和低温电子显微镜，非常适合于相对 无序的丝状集合体，如淀粉样蛋白。模型约束还将来自其他方法。 具体目标涉及A？、tau和PrP。人造脑和脑之间的结构和生物学差异- 衍生的Aü已被鉴定，但尚未被表征。Tau和PrP研究将解决最低限度的 需要一种自我传播的淀粉样蛋白。体内自我繁殖的样本分析将与 结构研究。

Summary: Project 2 Stubbs Many neurodegenerative diseases are associated with amyloid deposits, aggregates of misfolded proteins characterized by ß-strands extending roughly perpendicular to the axes of long, unbranched fibrils. Examples include Alzheimer's disease associated with the peptide Aß, Parkinson's disease associated with the protein α-synuclein, a number of diseases including Alzheimer's and chronic traumatic encephalopathy associated with the protein tau, and Creuzfeldt-Jakob and others associated with the mammalian prion protein PrP. These diseases have in common the property of self-propagation of the aberrant peptide fold, as originally recognized in the mammalian prions derived from PrP. The structural and self-propagating properties of the amyloid form of PrP are shared by other pathological amyloids, and these diseases are essentially all prion diseases. Molecular structure and structural transitions are thus the key to understanding these diseases, and eventually to designing diagnostic and therapeutic interventions. Knowledge of the amyloid structure will provide information about the precursor oligomers that have in many cases been identified as the toxic species, and share structural features with the fibrils. Knowledge of the amyloid structure combined with information about the oligomers (Projects 3, 4) will also increase understanding of the interconversion pathways that include the toxic species. The overall goal of this project is to determine the structures of amyloids associated with some of the most devastating neurodegenerative diseases. Amyloids are not conducive to crystallographic or solution NMR studies, so the primary approaches are fiber diffraction and cryo-electron microscopy, well suited to relatively disordered filamentous assemblies such as amyloids. Model restraints will also come from other methods. The specific aims address Aß, tau, and PrP. Structural and biological differences between synthetic and brain- derived Aß have been identified but not yet characterized. Tau and PrP studies will address the minimal requirement for a self-propagating amyloid. Sample assays for self-propagation in vivo will be correlated with the structural studies.