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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结