THE MOLECULAR BASIS OF ALPHA-SYNUCLEIN AGGREGATION

描述（来自申请人的摘要）：最近，α-突触核蛋白已经被发现。 作为路易体的主要成分， 这是帕金森病（PD）的病理标志。我们的目标是 他们的建议是检验帕金森病的关键步骤 是α-突触核蛋白的聚集，这导致了路易 最终导致神经元死亡。具体来说，我们将确定 α-突触核蛋白聚集的分子基础和研究潜力 α-突触蛋白聚集的抑制剂。 我们的初步研究结果揭示了一些导致 α突触核蛋白在中性pH下的构象变化，以及聚集 和原纤维形成。我们计划系统地描述 α-突触核蛋白的性质，以确定是否有一个相关性， 其构象和聚集倾向，与野生型和 突变的α-突触核蛋白。我们将研究各种因素是否与 与PD，例如，金属离子和农药，增强聚集 α-突触核蛋白将研究汇总过程的细节， 阐明聚集和纤维形成的分子机制。我们将 筛选一系列肽类和小分子， α-突触核蛋白聚集。 这些实验代表了阐明 帕金森氏病中的α-突触核蛋白我们希望了解潜在的作用 各种因素，从环境污染物到 α-突触核蛋白的浓度，在触发原纤维形成。我们还 预测发现抑制剂，这可能奠定了基础， 治疗方法。要使用的技术包括各种 生物物理/生物化学方法，如衰减全反射FTIR， 分析聚集的α-突触核蛋白的构象状态，原子力 和电子显微镜成像的聚集体，和动力学方法，以监测 纤维形成的速率。

DESCRIPTION (From the applicant's abstract): Recently,alpha-synuclein has been identified as a major component of Lewy bodies, the intracellular inclusions that are a pathological hallmark of Parkinson's disease (PD). Our goals in this proposal are to test the hypothesis that a critical step in Parkinson's disease is the aggregation of alpha-synuclein, which leads to the formation of Lewy Bodies and subsequently to neuronal death. Specifically we will determine the molecular basis for alpha-synuclein aggregation and investigate potential inhibitors of alpha-syouclein aggregation. Our preliminary results have revealed a number of factors that lead to a confonnational change in alpha synuclein at neutral pH, and also to aggregation and fibril formation. We plan a systematic characterization of the biophysical properties of alpha-synuclein to determine if there is a correlation between its conformation and its propensity to aggregate, with both wild type and mutant alpha-synucleins. We will investigate whether various factors associated with PD, for example, metal ions and pesticides, enhance the aggregation of alpha-synuclein. Details of the aggregation process will be studied to elucidate the molecular mechanism of aggregation and fibril formation. We will screen a series of peptides and small molecules for inhibitory effects on alpha-synuclein aggregation. These experiments represent critical steps towards elucidating the role of alpha-synuclein in Parkinson's disease. We expect to learn the potential role of various factors, ranging from environmental contaminants to the concentration of alpha-synuclein, in triggering fibril formation. Further, we anticipate fnding inhibitors which may lay the groundwork for potential therapeutic approaches. Techniques to be used include various biophysical/biochemical methods, such as attenuated total reflectance FTIR to analyze the conformaffonal state of aggregated alpha-synuclein, atomic force and electron microscopy to image the aggregates, and kinetic methods to monitor the rate of formation of fibrils.