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: 10228703
• 负责人: Heather R Lucas
• 金额: $ 33.01万
• 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/10228703
• 关键词: Affinity; Attention; Behavior; Benign; Binding; Binding Sites; Biochemical; Biochemical Process; Biochemistry; Biological; Biophysics; Brain; California; Cerebrum; Chemistry; Collaborations; Communities; Copper; Coupling; Deltastab; Deposition; Disease; Disease Pathway; Drug Targeting; Erythrocytes; Etiology; Evaluation; Event; Goals; Homo; Human; Hydrophobic Interactions; Image; Immunoblotting; Investigation; Iron; Knowledge; Laboratories; Lewy Bodies; Light; 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; Signaling Protein; Source; Structure; Symptoms; Techniques; Therapeutic; Toxin; Trace Elements; Transition Elements; Tyrosine; United States National Institutes of Health; Universities; Work; 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.

项目摘要 阐明蛋白质 - 金属相互作用的病理学一直是神经退行性的焦点 疾病研究多年。标志性蛋白α-突触核蛋白（αs），与最多有关 普遍的运动障碍 - 帕金森氏病（PD），在功能和功能方面尚不清楚 构象。同样，与过渡生物特征的作用（即铜和铁）有关的问题仍然是 一个神秘的。这项研究旨在阐明这些生物特征对αs不同构象状态的影响， 围绕天然结构的当前争议有助于清晰。近年来，同样令人信服 据报道，关于红细胞和脑衍生的αs蛋白的生化研究，该研究的主张是支持支持的 αs的两个不同天然构象。 αs的常规构象已被描述为 本质上受到干扰的单体可以自我结合形成有毒的低聚物以及与疾病相关的 不溶性的骨料称为路易尸体。最近的发现支持了天然四聚体α-螺旋αS 通过疏水相互作用稳定的构象，对聚集具有抗性 研究很少。关于铜和铁在这些天然构象中的作用的全面研究 考虑结构影响，膜亲和力，蛋白质 - 蛋白质相互作用和/或产生能力 功能性/功能失调的翻译后修饰尚未报告。跨学科 通过此研究策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/或硝化作用方面的进步 分子机制将有助于阐明与病理相关的疾病途径 使用PD并可能激发药物开发和/或临床生物标志物的新目标。