Structure and Function of alpha synuclein

描述（由申请人提供）：蛋白质α-突触核蛋白（aS）在细胞内起作用。 帕金森病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，有序聚集体的aS是细胞内的主要组成部分， 路易体沉积物是PD的特征，小鼠和果蝇表达人aS 为帕金森病提供了第一个转基因动物模型。的正常功能 aS仍然未知，但它被认为是一个突触囊泡相关的 蛋白aS经历构象变化，成为高度螺旋状态， 与脂质囊泡或SDS胶束相互作用，这种状态被认为是 代表了一种蛋白质，可能是几种正常功能的蛋白质之一， 构象 As在溶液中游离时本质上是非结构化的，但缓慢形成典型的 淀粉样纤维，类似于路易体中发现的纤维， 证实在PD中起因果作用。免费即服务中的剩余结构可能发挥作用 在介导分子间相互作用中起着重要作用， 淀粉样纤维形成，和早发性的aS突变可能发挥其 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 在其自由状态下使用NMIR光谱。我们亦建议在 详细介绍了SDS和脂质囊泡相关的aS的结构，以获得 了解这种蛋白质的正常结构和功能。我们会调查 早发性突变（A3 OP和A53 T）和新设计的aS 突变的结构和动力学在其自由和脂质相关的状态。我们 将试图描绘和表征涉及的具体网站， 导致aS原纤维形成初始寡聚化相互作用， 我将使用突变体来测试我们的结论，合作，在一个转基因苍蝇 PD模型 拟议的研究重点是提高我们对 帕金森病的分子机制，并可能建议发展战略， 新的帕金森病疗法研究结果可能对以下方面产生更广泛的影响： 了解和治疗其他淀粉样疾病，包括阿尔茨海默氏症 疾病和朊病毒疾病。

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.