Alpha-Synuclein Assemblies and Metal-Mediated Redox Mechanisms

项目摘要 阐明蛋白质-金属相互作用的发病机制一直是神经退行性疾病的焦点。 疾病研究多年。标志性蛋白α-突触核蛋白（αS），与大多数 流行的运动障碍-帕金森病（PD），在功能和 构象同样，关于过渡生物金属，即铜和铁的作用的问题仍然存在。 一个谜本研究旨在阐明这些生物金属对αS不同构象状态的影响， 有助于澄清当前围绕原生结构的争议。近年来，同样令人信服的 对红细胞和脑源性αS蛋白的生化研究已经报道，支持 αS的两种不同的天然构象。αS的常规构象被描述为一种 可以自缔合形成有毒低聚物以及疾病相关 称为路易体的不溶性聚集体。最近的研究结果支持天然的四聚体α-螺旋αS 通过疏水相互作用稳定的构象，并且抗聚集，但系统 研究是稀疏的。综合研究铜和铁在这些天然构象中的作用， 考虑到结构影响、膜亲和力、蛋白质-蛋白质相互作用和/或产生 功能性/功能障碍性翻译后修饰尚未报道。跨学科 通过本研究战略描述的方法将有助于缩小生物医学界的这一差距。 同样，在理解tau/αS相互作用以及氧化和/或亚硝化作用方面的进展， 分子机制将有助于阐明病理相关的疾病途径， 并且可能激发药物开发和/或临床生物标志物的新靶点。

PROJECT SUMMARY Elucidation of the etiopathology of protein-metal interactions has been in the spotlight of neurodegenerative disease research for many years. The hallmark protein α-synuclein (αS), which is associated with the most prevalent movement disorder - Parkinson’s disease (PD), remains unclear in regards to both function and conformation. Similarly, questions pertaining to the role of transition biometals, namely copper and iron, are still a mystery. This research aims to elucidate the effect of these biometals on different conformational states of αS, contributing clarity to current controversies surrounding the native structure. In recent years, equally convincing biochemical studies on erythrocyte- and brain-derived αS protein have been reported that argue in support of two different native conformations for αS. The conventional conformation of αS has been described as an intrinsically disordered monomer that can self-associate to form toxic oligomers as well as disease-relevant insoluble aggregates termed Lewy bodies. Recent findings have supported a native tetrameric α-helical αS conformation that is stabilized by hydrophobic interactions and that is resistant to aggregation, yet systematic studies are sparse. Comprehensive studies on the role of copper and iron in these native conformations in regards to structural influences, membrane affinity, protein-protein interactions, and/or ability to produce functional/dysfunctional post-translational modifications have yet to be reported. The cross-disciplinary approach described through this research strategy will aid in closing this gap within the biomedical community. Likewise, an advancement in the understanding of tau/αS interactions as well as oxidative and/or nitrosative molecular mechanisms will contribute to the elucidation of pathologically relevant disease pathways associated with PD and may inspire new targets for drug development and/or clinical biomarkers.