Understanding PDI-related neurotoxicity and advancing preventative approaches

了解 PDI 相关的神经毒性并推进预防方法

• 批准号: 9476277
• 负责人: Mahesh Narayan
• 金额: $ 11.33万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9476277
• 关键词: Address; Adverse effects; Alzheimer' s Disease; Antibodies; Attenuated; Autopsy; Behavioral; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Cadaver; Catalytic Domain; Cell Line; Cell model; Cells; Chemicals; Computer Simulation; Country; Cysteine; Data; Development; Diet; Disease; Dose; Dynamin; Ellagic Acid; Endoplasmic Reticulum; Event; Failure; Farming environment; Foundations; Functional disorder; Glyceraldehyde-3-Phosphate Dehydrogenases; Goals; Health; Hispanics; Housekeeping; Human; Huntington Disease; Knowledge; Lewy Bodies; Lewy Body Variant of Alzheimer' s Disease; Link; Manuscripts; Medical; Minor; Mitochondria; Modeling; Modification; Molecular Bank; Molecular Chaperones; Multiple System Atrophy; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Neuropathy; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Oxidoreductase; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathologic; Pharmacology; Phytochemical; Preparation; Production; Protein Disulfide Isomerase; Proteins; Rattus; Reaction; Reporting; Research; Research Design; Rodent; Rodent Model; Role; Rotenone; SKIL gene; SNCAIP gene; Sodium; Sorting - Cell Movement; Testing; Therapeutic; Variant; Wit; Work; alpha synuclein; analog; beta-Hydroxybutyrate; clinically relevant; clinically significant; design; disulfide bond; improved; misfolded protein; myocyte-specific enhancer-binding factor 2; neuroblastoma cell; neurotoxicity; nitrosative stress; overexpression; parkin gene/protein; pesticide exposure; pharmacophore; preservation; prevent; prophylactic; protein aggregate; protein biomarkers; protein expression; protein folding; protein misfolding; public health relevance; response; small molecule; success; synucleinopathy; x-linked inhibitor of apoptosis protein

 DESCRIPTION (provided by applicant): Protein disulfide isomerase (PDI) is an endoplasmic reticulum (ER)-resident oxidoreductase chaperone that catalyzes the maturation of disulfide-bond-containing proteins. S-nitrosylated PDI (SNO-PDI), which is the chemical modification of its catalytic cysteine in response to nitrosative stress, has been found in post-mortem brains of Parkinson's and Alzheimer's disease victims along with synphilin-1:alpha-synuclein protein aggregates (called Lewy Bodies). Additional studies in cells revealed that levels of SNO-PDI formation directly co-related with the aggregation and accumulation of the minor but critical Parkinsonian biomarker synphilin-1 in a NO-sensitive manner. While SNO-PDI formation leads to the accumulation of polyubiquitinated proteins, expression of native PDI (non-SNO-PDI) attenuates these effects in a Parkinsonian cell model. These data show that PDI is neuroprotective and underscore the need for functional preservation of PDI's catalytic activity as a key preventative approach to pathogenesis of nitrosative-stress-related Parkinson's. The data also suggest the involvement of PDI dysfunction in the pathogenesis of neuropathies such as the Lewy Body Variant of Alzheimer's (LBVAD) and Alzheimer's. However, there is still a gap in studies designed to determine whether other neurotoxicity-related biomarkers accumulate as a function of SNO-PDI formation. We hypothesize that SNO-PDI formation may provoke aggregation of alpha-synuclein, the major Parkinsonian and LBVAD biomarker protein and Lewy-body constituent. As a corollary to our hypothesis, it is possible that strategies designed to prevent SNO-PDI formation are neuroprotective and prophylactic to Parkinson's. The hypothesis will be tested by examining the aggregation of alpha-synuclein as a function of nitrosative insult in a cell line model. Furthermore, the translational feasibility of ellagic acid, Na-betahydroxybutyrate and Ferrostatin-1 analogs, which our lab has preliminarily demonstrated as being neuroprotective, will be assayed in a rotenone rat Parkinson model. The overall objective of this project it to lay the foundation for long-term work involving the development of pharmacologically relevant small molecule therapies that are neuroprotective by mitigating the effects of oxidative and nitrosative stress.

 描述（由应用提供）：蛋白质二硫异构酶（PDI）是一种内质网（ER） - 居民氧化还原酶链酮，可催化含二硫键键合蛋白的成熟。 S-硝基化的PDI（SNO-PDI）是对硝化应激的催化性半胱氨酸的化学修饰，在帕金森氏症和阿尔茨海默氏病后脑中的脑大脑中发现了滥用剂量，以及synphilin-1：alpha-synnuclein蛋白蛋白蛋白蛋白聚集（称为lew lewy hodies）。在细胞中的其他研究表明，SNO-PDI形成水平与次要但关键的帕金森氏症生物标志物Synphilin-1直接与无敏感的方式相关。尽管SNO-PDI的形成导致多泛素化蛋白的积累，但天然PDI（非SNO-PDI）的表达在帕金森氏细胞模型中减弱了这些作用。这些数据表明，PDI具有神经保护作用，并强调了将PDI催化活性作为硝酸压力相关帕金森氏症发病机理的关键预防方法的功能保存。数据还表明，PDI功能障碍参与神经病的发病机理，例如阿尔茨海默氏症（LBVAD）和阿尔茨海默氏症的Lewy身体变体。但是，研究中仍然存在差距，旨在确定其他与神经毒性相关的生物标志物是否会随着SNO-PDI形成的函数而积累。我们假设SNO-PDI形成可能会激发α-核蛋白，主要帕金森氏症和LBVAD生物标志物蛋白以及Lewy-Body构建体的构成。作为我们假设的推论，旨在旨在的策略可能 防止SNO-PDI形成是神经保护性的，并且对帕金森氏病具有预防性。该假设将通过检查α-突触核蛋白的聚集来检验，这是细胞系模型中亚硝化损伤的函数。此外，椭圆酸，Na-甲基二羟基丁酸和亚铁蛋白-1类似物的转化可行性（我们的实验室最初证明是神经保护性）将被分配在rotorone大鼠帕克森模型中。该项目的总体目标是为长期工作奠定基础，包括通过减轻氧化和硝化应激的影响来开发具有神经保护性的药物相关的小分子疗法。