MPO oxidants in synucleinopathies

突触核蛋白病中的 MPO 氧化剂

基本信息

批准号：
8239611
负责人：
WANDA F REYNOLDS
金额：
$ 40.09万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8239611
关键词：
Address Alu Elements Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Precursor Astrocytes Autophagocytosis Autopsy Binding Sites Biological Assay Brain California Cells Cessation of life Corpus striatum structure Dopamine Electron Transport Experimental Pathology Feedback Gene Expression Generations Genes Goals Head Human Hypochlorous Acid Immune system In Vitro Inclusion Bodies Infection LRRK2 gene Laboratories Lewy Bodies Memory impairment Methodology Mitochondria Modeling Mus Myelogenous Nervous System Trauma Neuronal Dysfunction Neurons Nitrates Nitric Oxide Normal Cell Nuclear Receptors Oxidants Oxidative Stress Oxidopamine PTEN gene Parkinson Disease Pathology Pattern Peroxidases Phospholipids Primates Proteins Resistance Role Rotenone Screening procedure Site Small Interfering RNA Source Staging Stress Substantia nigra structure Symptoms Tissues Toxin Transgenic Model Transgenic Organisms Tyrosine 3-Monooxygenase Universities alpha synuclein alpha synuclein gene authority base behavioral impairment case control dimer dopaminergic neuron enzyme activity member monocyte motor impairment mouse model mutant neuroblastoma cell neuron loss neurotoxic neutrophil new therapeutic target nitration overexpression oxidation parkin gene/protein pars compacta peroxidation promoter research study small molecule synuclein synucleinopathy transcription factor

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) with accumulation of a-synuclein (a-syn) in aggregates and Lewy bodies. Oxidative stress is implicated as a causative factor. Nitration of a-syn promotes misfolding and formation of aggregates resistant to clearance by autophagy. Our studies suggest that myeloperoxidase (MPO) is a significant source of oxidants that promote misfolding and aggregation of a-syn, as well as oxidation/nitration of other proteins implicated in the pathology of PD. MPO is a component of the armamentarium of the innate immune system, released by neutrophils and monocytes at sites of infection where it produces the potent oxidant, hypochlorous acid (HOCl) while reacting with nitric oxide to generate reactive nitrating species. MPO oxidants also damage normal cells, such that expression is normally restricted to myeloid precursors. However, the human MPO gene (huMPO) is able to escape this restriction, in that MPO is aberrantly expressed in subsets of neurons and astrocytes in Alzheimer's disease (AD). MPO is also aberrantly expressed in PD SNpc, and in vitro studies showed that MPO promotes nitration of a-syn leading to dimers and oligomers. The aims of this proposal are to (1) Investigate the oxidative and pathological consequences of MPO expression in mouse models of synucleinopathies. (2) Evaluate human PD tissue to establish the expression patterns of MPO and the oxidative consequences. (3) Investigate the role of MPO in synucleinopathies in vitro using SHSY5Y neuroblastoma cells stably expressing a-syn. PUBLIC HEALTH RELEVANCE: Current treatments for Parkinson's disease ameliorate the symptoms but do not reduce the progressive loss of neurons. These studies may provide evidence that MPO oxidants contribute to PD pathology, identifying MPO as a novel therapeutic target. Screening studies could identify small molecule antagonists that reduce neurological damage if provided at early stages of PD.

描述（由申请人提供）：帕金森氏病（PD）的特征在于黑质致密部（SNpc）中多巴胺能（DA）神经元的丧失以及α-突触核蛋白（a-syn）在聚集体和路易体中的积累。氧化应激被认为是一个致病因素。 a-syn 的硝化会促进错误折叠和形成抗自噬清除的聚集体。我们的研究表明，髓过氧化物酶 (MPO) 是氧化剂的重要来源，可促进 a-syn 的错误折叠和聚集，以及与 PD 病理有关的其他蛋白质的氧化/硝化。 MPO 是先天免疫系统的组成部分，由中性粒细胞和单核细胞在感染部位释放，产生强效氧化剂次氯酸 (HOCl)，同时与一氧化氮反应生成活性硝化物质。 MPO 氧化剂也会损害正常细胞，因此表达通常仅限于骨髓前体细胞。然而，人类 MPO 基因 (huMPO) 能够逃脱这种限制，因为 MPO 在阿尔茨海默病 (AD) 的神经元和星形胶质细胞亚群中异常表达。 MPO 在 PD SNpc 中也异常表达，体外研究表明 MPO 促进 a-syn 硝化，形成二聚体和寡聚体。该提案的目的是 (1) 研究突触核蛋白病小鼠模型中 MPO 表达的氧化和病理后果。 (2) 评估人PD组织以确定MPO的表达模式和氧化后果。 (3) 使用稳定表达a-syn的SHSY5Y神经母细胞瘤细胞体外研究MPO在突触核蛋白病中的作用。公共健康相关性：目前帕金森病的治疗可以改善症状，但不能减少神经元的进行性损失。这些研究可能提供 MPO 氧化剂导致 PD 病理学的证据，从而将 MPO 确定为新的治疗靶点。筛选研究可以识别小分子拮抗剂，如果在帕金森病的早期阶段提供，可以减少神经损伤。