Structure and Function of alpha synuclein

描述(申请人提供)：蛋白a-突触核蛋白(AS)在 帕金森病发病机制中重要但知之甚少的作用 (Pd)。遗传性早发性帕金森病的突变可追溯到AS 基因，AS的有序聚集体是细胞内的主要成分 路易小体沉积具有帕金森病特征，小鼠和苍蝇表达人AS 为帕金森病提供了首个转基因动物模型。的正常功能 AS仍不清楚，但它被认为是与突触小泡相关的 蛋白。当经历构象变化到高度螺旋状态时 与脂泡或十二烷基硫酸钠胶束相互作用，这种状态被认为 代表蛋白质在可能的几种正常功能中的一种 构象。 AS在溶液中游离时本质上是无结构的，但慢慢形成典型的 淀粉样纤维，类似于在路易小体中发现的那些， 推测在帕金森病中起因果作用。自由发挥中的残余结构 在调解之前的分子间相互作用中发挥的重要作用 淀粉样蛋白原纤维的形成，以及早发性AS突变可能会发挥其作用 通过调节这种残留结构而产生的致病作用。我们建议 在高分辨率下表征As的结构和动力学性质 使用NMIR光谱分析其自由态。我们还建议在 详细说明与十二烷基硫酸钠和脂泡相关的AS的结构，以便获得 对这种蛋白质的正常结构和功能的洞察。我们会调查 早发性突变(A3OP和A53T)和新设计的AS的影响 在其自由和脂质相关状态下的结构和动力学上的突变。我们 将尝试描绘和描述参与 最初的齐聚相互作用会导致AS纤维的形成，而我们 将在转基因果蝇中合作使用突变体来测试我们的结论 帕金森病模型。 建议的研究重点是加深我们对 帕金森病的分子机制和可能的发展策略 新的帕金森病疗法。结果可能会对以下方面产生更广泛的影响 了解和治疗其他淀粉样蛋白疾病，包括阿尔茨海默氏症 疾病和Pron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.