Alpha-Synuclein Assemblies and Metal-Mediated Redox Mechanisms

α-突触核蛋白组装和金属介导的氧化还原机制

• 批准号: 10688195
• 负责人: Heather R Lucas
• 金额: $ 32.93万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688195
• 关键词: Acetylation; Affinity; Attention; Behavior; Benign; Binding; Binding Sites; Biochemical; Biochemical Process; Biochemistry; Biophysics; Brain; California; Cerebrum; Chemistry; Collaborations; Communities; Copper; Coupling; Deposition; Disease; Disease Pathway; Drug Targeting; Electronics; Erythrocytes; Etiology; Evaluation; Event; Goals; Homo; Human; Hydrophobic Interactions; Image; Investigation; Iron; Knowledge; Laboratories; Lewy Bodies; Link; Mass Spectrum Analysis; Mediating; Membrane; Metal Binding Site; Metals; Methods; Molecular; Molecular Conformation; Movement Disorders; N-terminal; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Neurodegenerative Disorders; Neurons; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Physiological; Population; Post-Translational Protein Processing; Process; Protein Conformation; Protein Dynamics; Proteins; Protocols documentation; Publishing; Reaction; Recombinants; Reporting; Research; Research Personnel; Research Proposals; Resistance; Role; Signal Transduction; Source; Structure; Symptoms; Techniques; Therapeutic; Toxin; Trace Elements; Transition Elements; Tyrosine; United States National Institutes of Health; Universities; Western Blotting; Work; alpha helix; alpha synuclein; beta pleated sheet; biological systems; brain tissue; clinical biomarkers; cofactor; conformer; crosslink; dityrosine; drug development; in vivo; ion mobility; light scattering; metal complex; monomer; mutant; nanoscale; new therapeutic target; nitrosative stress; protein aggregation; protein distribution; protein misfolding; protein protein interaction; tau Proteins

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.

项目概要 阐明蛋白质-金属相互作用的病因病理学一直是神经退行性疾病的焦点 多年疾病研究。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)，其功能和功能仍不清楚 构象。同样，与过渡生物金属（即铜和铁）的作用有关的问题仍然存在。 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 据报道，对红细胞和脑源性 αS 蛋白的生化研究支持以下观点： αS 的两种不同的天然构象。 αS的常规构象被描述为 本质上无序的单体，可以自缔合形成有毒的低聚物以及与疾病相关的低聚物 不溶性聚集体称为路易体。最近的研究结果支持天然四聚体 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 研究很少。综合研究铜和铁在这些天然构象中的作用 关于结构影响、膜亲和力、蛋白质-蛋白质相互作用和/或生产能力 功能性/功能障碍性翻译后修饰尚未有报道。跨学科 通过该研究策略描述的方法将有助于缩小生物医学界内的这一差距。 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 与 PD 相关，可能会激发药物开发和/或临床生物标志物的新目标。