Copper binding to the physiological form of the alpha-synuclein protein

人α-突触核蛋白（AS）蛋白与帕金森病（PD）和其他神经退行性疾病的发病机制有关。在PD中，AS是路易体的主要成分，路易体是黑质（中脑的一部分）中的蛋白质存款。AS蛋白自聚集的原因和机制尚不清楚。铜离子被发现在阿尔茨海默病中是有害的，它加速了AS的非生理性、非乙酰化形式在水溶液中的聚集，其中蛋白质是自然展开的。Cu（I）和Cu（II）离子可能在PD相关的神经元紊乱中起作用。虽然对非乙酰化、非生理形式的结构见解是可用的，但缺乏对生理相关乙酰化形式（AcAS）的结构见解。然而，Cu（I）-AS形式的光谱性质与Cu（I）-AcAS的光谱性质非常相似。因此，关于Cu（I）-AS的结构研究的结论对于Cu（I）-AcAS基本上仍然有效。这与Cu（II）与AcAS的结合形成对比，其与AS的结合完全不同。在这里，我们计划预测Cu（II）-AcAS的结构决定因素的分子模拟。计算的NMR、EXAFS和CD谱与我们的合作者Claudio费尔南德斯为这项研究测量的实验谱之间的比较将建立我们预测的可靠性。我们的研究可能会提供第一个有价值的新见解，金属，特别是铜，如何调节AS原纤维形成过程。这对于开发新的药物设计方法至关重要。

The human alpha-synuclein (AS) protein is associated with the pathogenesis of Parkinsons disease (PD) and other neurodegenerative disorders. In PD, AS is the primary component of Lewy-bodies, a proteinaceous deposit in the substantia nigra (a part of the midbrain). The causes and mechanisms of the self-aggregation of AS protein are unknown. Copper ions, which are found to be harmful in Alzheimers disease, accelerate aggregation of the non-physiological, non-acetylated form of AS in aqueous solution, where the protein is naturally unfolded. Both Cu(I) and Cu(II) ions may play a role in the neuron derangement associated with PD. While structural insights on the non-acetylated, non-physiological form are available, those on the physiologically relevant acetylated form (AcAS) are lacking. However, spectral properties of the Cu(I)-AS form are very similar to the ones of Cu(I)-AcAS. Thus, the conclusions of structural studies regarding Cu(I)-AS remain basically valid for Cu(I)-AcAS. This contrasts with Cu(II) binding to AcAS, which is completely different from that to AS. Here we plan to predict Cu(II)-AcAS structural determinants by molecular simulation. Comparison between calculated NMR, EXAFS and CD spectra and the experimental ones, measured by our collaborator Claudio Fernandez for this research, will establish the reliability of our predictions. Our study may provide the first valuable new insights on how metals, in particular copper, modulate AS fibril formation process. This could be crucial for the development of new drug-design approaches.