Structure and Function of Alpha-Synuclein

α-突触核蛋白的结构和功能

• 批准号: 7047811
• 负责人: David Eliezer
• 金额: $ 30.27万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047811
• 关键词: Drosophilidae; Lewy body; Parkinson' s disease; alpha synuclein; amyloid proteins; autosomal dominant trait; biophysics; conformation; covalent bond; gene mutation; genetic models; genetically modified animals; intermolecular interaction; micelles; nerve /myelin protein; neural degeneration; neurogenetics; nuclear magnetic resonance spectroscopy; protein protein interaction; protein structure function; synaptic vesicles; yeasts

DESCRIPTION (provided by applicant): Aggregation of a-synuclein (aS) plays an important but still poorly understood role in the pathogenesis of Parkinson's disease (PD). The normal function of aS remains unknown, but the protein binds to phospholipid membranes and is believed to regulate synaptic vesicle pool size, vesicle recycling, neurotransmitter transport and release, and synaptic plasticity. Since the discovery of the link between aS and PD, there has been great interest in identifying aS interaction partners that influence either the pathogenic or normal roles of the protein. In the past few years, a growing number of proteins, polymers, and small molecules have been reported to bind to aS and alter its aggregation kinetics and/or its lipid-associated functions. Among these are two other members of the synuclein family, B-synuclein (BS) and y-synuclein (yS). Covalent modifications also affect aS aggregation and function. However, the mechanisms by which these various binding interactions and modifications influence aS behavior are not well understood. We have shown that residual structure in free aS may play an important role in mediating the intermolecular interactions that precede amyloid fibril formation by this protein. We hypothesize that upon covalent modification or partner interactions, aS undergoes conformational changes that underlie the consequent effects on the aggregation or normal functions of the protein. We therefore propose to characterize, at high resolution, the structural changes that occur in aS as a function of its modifications and its interactions with different partners, with an initial focus on (BS, yS, histones, HSP70, PLD2, copper and other metals and polycations. We also propose to elucidate in detail the structure of (BS and yS in their free and lipid-bound states to clarify why aS exhibits different self-assembly behavior from these close relatives. Finally, we plan to test our conclusions regarding the role of structural changes in aS by introducing rationally designed mutants, collaboratively, into yeast and fly models of aS toxicity and function. 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）：α-突触核蛋白（aS）的聚集在帕金森病（PD）的发病机制中发挥着重要但仍知之甚少的作用。 aS 的正常功能仍不清楚，但该蛋白与磷脂膜结合，被认为可以调节突触小泡池大小、小泡回收、神经递质运输和释放以及突触可塑性。自从发现 aS 和 PD 之间的联系以来，人们对鉴定影响蛋白质致病或正常作用的 aS 相互作用伙伴产生了极大的兴趣。在过去的几年中，据报道越来越多的蛋白质、聚合物和小分子与 aS 结合并改变其聚集动力学和/或其脂质相关功能。其中包括突触核蛋白家族的另外两个成员：B-突触核蛋白 (BS) 和 y-突触核蛋白 (yS)。共价修饰也会影响 aS 聚集和功能。然而，这些不同的结合相互作用和修饰影响 aS 行为的机制尚不清楚。我们已经证明，游离 aS 中的残留结构可能在介导该蛋白质形成淀粉样原纤维之前的分子间相互作用中发挥重要作用。我们假设，在共价修饰或伴侣相互作用后，aS 会发生构象变化，从而对蛋白质的聚集或正常功能产生后续影响。因此，我们建议以高分辨率表征 aS 中发生的结构变化，作为其修饰及其与不同伙伴相互作用的函数，最初重点关注（BS、yS、组蛋白、HSP70、PLD2、铜和其他金属）我们还建议详细阐明 (BS 和 yS 在游离状态和脂质结合状态下的结构，以阐明为什么 aS 表现出与这些近亲不同的自组装行为。最后，我们计划进行测试。我们通过将合理设计的突变体合作引入酵母和苍蝇模型的 aS 毒性和功能来得出关于 aS 结构变化的作用的结论。拟议的研究重点是提高我们对 PD 分子机制的理解，并可能提出开发策略。新的帕金森病疗法。这些结果可能对理解和治疗其他淀粉样蛋白疾病（包括阿尔茨海默氏病和朊病毒病）具有更广泛的影响。