MPO oxidants in synucleinopathies

突触核蛋白病中的 MPO 氧化剂

基本信息

批准号：
8499445
负责人：
WANDA F REYNOLDS
金额：
$ 36.94万
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/8499445
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 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 screening 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.

描述（由申请人提供）：帕金森氏病（PD）的特征是底虫nigra pars comcacta（SNPC）中多巴胺能（DA）神经元的丧失，聚集体中A-突触核蛋白（A-synn）积聚。氧化应激被视为病因。 A-Syn的硝化促进了自噬对清除抗清除率的骨料的错误折叠和形成。我们的研究表明，髓过氧化物酶（MPO）是促进A-SYN的错误折叠和聚集的重要来源，以及与PD病理有关的其他蛋白质的氧化/氧化/硝化。 MPO是先天性免疫系统的武器群的组成部分，由中性粒细胞和单核细胞在感染部位释放，在该部位产生有效的氧化剂，次甲酸（HOCL），同时与一氧化氮反应以产生反应性硝化物质。 MPO氧化剂还会损害正常细胞，因此表达通常仅限于髓样前体。但是，人类MPO基因（Humpo）能够逃脱这一限制，因为MPO在阿尔茨海默氏病（AD）中在神经元和星形胶质细胞的子集中异常表达。 MPO在PD SNPC中也异常表达，并且体外研究表明，MPO促进了A-syn的硝化，导致二聚体和低聚物。该提案的目的是（1）研究突触核苷的小鼠模型中MPO表达的氧化和病理后果。（2）评估人类PD组织以建立MPO的表达模式和氧化后果。（3）研究MPO在体外使用SHSY5Y神经母细胞瘤细胞在体外稳定表达A-syn的作用。