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Integrating pathogenic mechanisms in Parkinson's disease

整合帕金森病的致病机制

基本信息

批准号：
10682994
负责人：
RAYMOND A SWANSON
金额：
$ 7.86万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10682994
关键词：
ABL1 gene Affect Binding Catecholamines Cell Culture Techniques Cell Respiration Cells Chronic Cysteine DNA Damage DNA Sequence Alteration Environmental Risk Factor Enzymes Esters Etiology Evaluation Genetic Glutathione Glutathione Disulfide Human Impairment Inflammation Inflammatory Knowledge Lead Link Metals Mitochondria Modeling Monitor Mouse Strains Mus NADPH Oxidase Neurons Oral Oxidation-Reduction Oxidative Stress Oxides Parkinson Disease Pathogenesis Pathogenicity Pathology Pathway interactions Peroxides Pharmacology Process Production Protein Tyrosine Kinase Proteins Quality Control Reactive Oxygen Species Sulfhydryl Compounds Superoxides Testing Therapeutic Tissues Toxin Transgenic Mice Transition Elements alpha synuclein disease phenotype excitatory amino acid transporter 3 in vivo mitochondrial dysfunction mouse model multicatalytic endopeptidase complex neuron loss novel novel therapeutics overexpression oxidant stress oxidation oxidative damage repaired response tool

项目摘要

ABSTRACT α-synuclein expression, c-Abl activation, and neuronal glutathione levels are each recognized as contributory factors in Parkinson’s disease, but how these factors interact is poorly understood. This knowledge gap is of basic and therapeutic relevance because these interactions may define a final common pathway in Parkinson’s disease pathogenesis. Glutathione is used by neurons to both scavenge reactive oxygen species and repair oxidatively damage proteins. In Parkinson’s disease, the accumulation of α- synuclein oligomers is associated with glutathione depletion, oxidative stress, and neuronal death. α-synuclein aggregate formation is promoted by c-Abl, a tyrosine kinase that is in turn activated by oxidative stress. We hypothesize that α-synuclein aggregates drive reactive oxygen species formation through metal-catalyzed processes, and that the resulting glutathione depletion contributes to α-synuclein aggregation and c-Abl activation in a feed-forward manner. We will test this hypothesis using cell culture models in which α- synuclein aggregates, thiol redox state, and c-Abl activity can be independently manipulated and monitored. We will also employ two novel double-transgenic mouse strains that permit evaluation of a-synuclein aggregation and its associated pathology in the setting of (1) deficient NADPH oxidase activity, and (2) reduced neuronal glutathione levels. These strains, in combination with novel pharmacological tools, will allow us to identify cause- effect relationships between neuronal oxidative stress, α-synuclein aggregation, and c-Abl activity in vivo. 1

摘要 α-突触核蛋白表达、c-Abl激活和神经元谷胱甘肽水平分别为被认为是帕金森病的促成因素，但这些因素如何相互作用，不太了解。这种知识差距具有基本和治疗意义，因为这些相互作用可能定义了帕金森病的最终共同途径发病机制谷氨酸被神经元用来抑制活性氧并修复氧化损伤的蛋白质。在帕金森病中，α- 突触核蛋白寡聚体与谷胱甘肽耗竭、氧化应激和神经元损伤有关。死亡α-突触核蛋白聚集体的形成由c-Abl促进，c-Abl是一种酪氨酸激酶，由氧化应激激活。我们假设α-突触核蛋白聚集体驱动通过金属催化过程形成活性氧，由此产生的谷胱甘肽耗竭有助于α-突触核蛋白聚集和c-Abl活化，前馈方式。我们将使用细胞培养模型来检验这一假设，其中α- 突触核蛋白聚集体、巯基氧化还原状态和c-Abl活性可以独立操纵并受到监控。我们还将采用两种新的双转基因小鼠品系， α-突触核蛋白聚集及其相关病理学的评价（1） NADPH氧化酶活性缺乏，和（2）神经元谷胱甘肽水平降低。这些菌株，结合新的药理学工具，将使我们能够确定原因- 神经元氧化应激、α-突触核蛋白聚集和c-Abl之间的效应关系体内活性。 1