Structure and Function of alpha synuclein

α突触核蛋白的结构和功能

• 批准号: 6726144
• 负责人: David Eliezer
• 金额: $ 27.29万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6726144
• 关键词: Drosophilidae; Lewy body; Parkinson' s disease; alpha synuclein; amyloid proteins; autosomal dominant trait; conformation; gene mutation; genetically modified animals; micelles; neural degeneration; neurogenetics; nuclear magnetic resonance spectroscopy; protein structure function; synaptic vesicles

DESCRIPTION (Provided by the Applicant): The protein a-synuclein (aS) plays an important but poorly understood role in the pathogenesis of Parkinson's disease (PD). Mutations found in hereditary early-onset PD have been traced to the aS gene, ordered aggregates of aS are the primary component of the intracellular Lewy body deposits characteristic of PD, and mice and flies expressing human aS have provided the first transgenic animal models for PD. The normal function of aS remains unknown, but it is believed to be a synaptic vesicle-associated protein. aS undergoes a conformational change to a highly helical state upon interacting with lipid vesicles or SDS micelles, and this state is thought to represent the protein in one of possibly several normally functioning conformations. As is intrinsically unstructured when free in solution but slowly forms typical amyloid fibrils, similar to those that are found in Lewy bodies and are conjectured to play a causal role in PD. Residual structure in free aS may play an important role in mediating the intermolecular interactions that precede amyloid fibril formation, and the early-onset aS mutations may exert their pathogenic effects by modulating such residual structure. We propose to characterize, at high resolution, the structural and dynamic properties of aS in its free state using NMIR spectroscopy. We also propose to elucidate in detail the structure of SDS - and lipid vesicle-associated aS in order to gain insights into the normal structure and function of this protein. We will probe the effects of early-onset mutations (A3OP and A53T) and of newly designed aS mutations on structure and dynamics in its free and lipid-associated states. We will attempt to delineate and characterize specific sites involved in the initial oligomerization interactions that lead to aS fibril formation, and we will use mutants to test our conclusions, collaboratively, in a transgenic fly model of PD. The proposed studies are focused on improving our understanding of the molecular mechanisms underlying PD and may suggest strategies for developing new PD therapeutics. The results may have broader implications for understanding and treating other amyloid diseases, including Alzheimer's disease and the prion diseases.

描述（由申请人提供）：蛋白质 a-突触核蛋白 (aS) 发挥着 在帕金森病的发病机制中重要但知之甚少的作用 （PD）。遗传性早发性 PD 中发现的突变可追溯到 aS 基因，aS的有序聚集体是细胞内的主要成分 路易体沉积了 PD 的特征，小鼠和果蝇表达了人类 aS 提供了第一个PD转基因动物模型。正常功能为 aS 仍然未知，但据信它是一种突触小泡相关的 蛋白质。 aS 经历构象变化至高度螺旋状态 与脂质囊泡或 SDS 胶束相互作用，这种状态被认为 代表可能几种正常功能之一中的蛋白质 构象。 当游离在溶液中时本质上是非结构化的，但慢慢形成典型的 淀粉样原纤维，与路易体中发现的类似， 据推测在PD中起因果作用。免费AS中的残差结构可以玩 在介导分子间相互作用中发挥重要作用 淀粉样原纤维的形成，早发的 aS 突变可能会发挥其作用 通过调节这种残留结构来产生致病作用。我们建议 以高分辨率表征 aS 的结构和动态特性 使用 NMIR 光谱法测定其游离状态。我们还建议阐明 详细描述 SDS 和脂质囊泡相关的 aS 的结构，以获得 深入了解该蛋白质的正常结构和功能。我们将探究 早发突变（A3OP 和 A53T）和新设计的 aS 的影响 其游离状态和脂质相关状态的结构和动力学突变。我们 将尝试描绘和描述涉及的具体地点 最初的寡聚相互作用导致 aS 原纤维形成，我们 将使用突变体在转基因果蝇中合作测试我们的结论 PD 模型。 拟议的研究重点是提高我们对 PD 的分子机制，并可能提出开发策略 新的PD疗法。结果可能具有更广泛的影响 了解和治疗其他淀粉样蛋白疾病，包括阿尔茨海默病 病和朊病毒病。