Alpha-Synuclein Assemblies and Metal-Mediated Redox Mechanisms

项目总结 蛋白质-金属相互作用的发病机制一直是神经退行性疾病研究的热点。 多年来对疾病的研究。标志蛋白α-突触核蛋白(αS)，与大多数 普遍存在的运动障碍-帕金森氏病(PD)，目前仍不清楚其功能和功能 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， 为当前围绕本土结构的争议提供了澄清。近年来，同样令人信服的是 据报道，对红细胞和脑源性αS蛋白的生化研究支持 αS有两种不同的天然构象。αS的传统构象被描述为 本质上无序的单体，可自缔合形成有毒低聚物以及与疾病相关的 不可溶的集合体称为路易体。最近的发现支持天然的四聚体α-螺旋αS 通过疏水相互作用稳定的、抗聚集的、但系统的构象 研究很少。铜和铁在这些天然构象中作用的综合研究 关于结构影响、膜亲和力、蛋白质-蛋白质相互作用和/或产生 功能/功能失调的翻译后修饰尚未报道。跨学科 通过这一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，对tau/αS相互作用以及氧化和/或亚硝化的理解也取得了进展 分子机制将有助于阐明相关的病理相关疾病途径。 并可能激发药物开发和/或临床生物标记物的新靶点。

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.