Alpha-Synuclein-Metal Complexes and Oxidative Stress in Parkinson's Disease

帕金森病中的α-突触核蛋白-金属复合物和氧化应激

基本信息

批准号：
7945319
负责人：
FEIMENG ZHOU
金额：
$ 36.13万
依托单位：
CALIFORNIA STATE UNIVERSITY LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7945319
关键词：
Adsorption Affinity Alzheimer&apos s Disease American Amino Acids Amyloid Analytical Chemistry Antioxidants Anus Area Ascorbic Acid Atomic Force Microscopy Attention Award Behavior Binding Binding Sites Biochemical Biochemistry Bioinorganic Chemistry Biological Assay Biomedical Research Brain Cell membrane Cells Cerebrospinal Fluid Charge Chemicals Chemistry China Circular Dichroism Collaborations Complex Cytoplasm DNA Data Department of Energy Deposition Development Disease Dissociation Doctor of Philosophy Dopamine Dopaminergic Cell Educational workshop Electrochemistry Electron Spin Resonance Spectroscopy Electron Transport Complex III Etiology Evaluation Faculty Fellowship Flavonoids Fluorescence Foundations Funding Funding Category Glean Glutathione Glycine Grant Grant Review Herbicides Huntington Disease Hydrogen Peroxide Hydroxyl Radical In Vitro Ion Channel Ions Israel Journals Kansas Kinetics Knowledge Laboratories Lead Learning Letters Lewy Bodies Ligand Binding Link Mainstreaming Manuscripts Mass Spectrum Analysis Measurement Measures Medical Mentors Metal Ion Binding Metals Methodology Migraine Minority Minority-Serving Institution Modification Molecular Molecular Structure Motivation Nature Neurodegenerative Disorders Neurons Neurotransmitters Nucleic Acids Outcome Oxidation-Reduction Oxidative Stress Oxygen Paper Parkinson Disease Patients Peptides Petroleum Pharmaceutical Preparations Play Process Production Productivity Property Proteins Publications Publishing Pyrones Rationalization Reaction Reactive Oxygen Species Research Research Activity Research Institute Research Personnel Risk Factors Role Science Scientist Site-Directed Mutagenesis Societies Spectrophotometry Spectrum Analysis Staging Structure Structure-Activity Relationship Students Surface System Techniques Toxic effect Toxin Training Transferrin Universities Work Writing adduct alpha synuclein base disorder risk dopaminergic neuron experience graduate student improved in vivo innovation insight instrumentation interest knowledge base light scattering member metal complex mutant neuromelanin neuropathology neurotoxicity next generation oxidation p53 gene/protein prevent professor programs public health relevance skills stem stoichiometry

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive neurodegenerative disorder underscored by the gradual loss of dopaminergic neurons in disease-inflicted brains. The major inclusion in degenerating dopaminergic cells (Lewy bodies) contains aggregates of the a-synuclein (a-syn) protein. The Fe(III) concentration in the cytoplasm of dopaminergic cells and Cu(II) content in cerebral spinal fluid of PD patients are both elevated. The oxidative stress hypothesis, which contends that complexes formed between a-syn and redox active metal ions could impose oxidative stress on neuronal cells, has gained widespread attention. The broad, long-term objective of this proposal is to rationalize the various redox reactions involving a-syn-metal complexes and cytosolic species (e.g., dopamine, glutathione, and ascorbic acid) in the development of oxidative stress and damage. The motivation behind the proposed study is that the inconsistencies in the current oxidative stress hypothesis stem largely from the lack of knowledge of the redox potentials of the a-syn-metal complexes and a detailed understanding of the reactions that produce reactive oxygen species (ROS). The specific aims include (1) studying the binding of Fe(III) and Cu(II) to wild-type and mutant a-syn molecules and the redox properties of the resultant complexes, (2) probing the kinetics of the ROS-producing reactions that involve these a-syn-metal complexes, and (3) examining the aggregation behaviors of a-syn in the presence of Fe(III) or Cu(II) and evaluating the neurotoxicity of the resultant aggregates. The kinetic studies of the a-syn-metal complexes or metal-containing a-syn aggregates in the presence of exogenous species (e.g., antioxidants such as flavonoids or PD risk factors such as herbicides) will also be conducted. A variety of analytical techniques (e.g., NMR, EPR, voltammetry, fluorescence, and adsorption spectroscopy) will be used to investigate the binding and redox reactions, whereas atomic force microscopy, circular dichroism, and dynamic light scattering will be employed to follow the aggregation processes. PUBLIC HEALTH RELEVANCE: The study will provide insight into the possible roles played by Fe(III), Cu(II), and a-synuclein in the etiology of Parkinson's disease (PD). The results are expected to lead to a better understanding of the associated molecular mechanisms, the modification of which might prevent or alleviate the neuropathological effects of PD. Furthermore, given the variety of techniques proposed and the interdisciplinary nature of this high-impact research, the work will play a significant part in training the next generation of researchers at a minority-serving institution.

描述（由申请人提供）：帕金森病（PD）是一种进行性神经退行性疾病，其特征是患病大脑中多巴胺能神经元的逐渐丧失。退化多巴胺能细胞（路易体）中的主要内含物含有 a-突触核蛋白 (a-syn) 蛋白的聚集体。 PD患者多巴胺能细胞胞质中Fe(III)浓度和脑脊液中Cu(II)含量均升高。氧化应激假说认为α-syn和氧化还原活性金属离子之间形成的复合物可以对神经元细胞施加氧化应激，该假说已引起广泛关注。该提案的广泛、长期目标是合理化氧化应激和损伤发展过程中涉及α-顺式金属络合物和胞质物质（例如多巴胺、谷胱甘肽和抗坏血酸）的各种氧化还原反应。拟议研究背后的动机是，当前氧化应激假说的不一致很大程度上源于缺乏对a-syn-金属配合物氧化还原电位的了解以及对产生活性氧（ROS）的反应的详细了解。。具体目标包括 (1) 研究 Fe(III) 和 Cu(II) 与野生型和突变型 a-syn 分子的结合以及所得复合物的氧化还原特性，(2) 探讨 ROS 产生的动力学涉及这些 a-syn-金属络合物的反应，以及 (3) 检查 a-syn 在 Fe(III) 或 Cu(II) 存在下的聚集行为，并评估所得聚集体的神经毒性。还将在存在外源物质（例如类黄酮等抗氧化剂或除草剂等 PD 危险因素）的情况下对 α-syn-金属配合物或含金属 α-syn 聚集体进行动力学研究。将使用各种分析技术（例如 NMR、EPR、伏安法、荧光和吸附光谱）来研究结合和氧化还原反应，而原子力显微镜、圆二色性和动态光散射将用于跟踪聚集流程。公共健康相关性：该研究将深入了解 Fe(III)、Cu(II) 和 a-突触核蛋白在帕金森病 (PD) 病因学中可能发挥的作用。预计这些结果将有助于更好地理解相关的分子机制，对其进行修改可能会预防或减轻帕金森病的神经病理学影响。此外，考虑到所提出的技术的多样性以及这项高影响力研究的跨学科性质，这项工作将在培训少数族裔服务机构的下一代研究人员方面发挥重要作用。