Involvement of Oxidative Stress in Occurrence of Relapses in Multiple Sclerosis: The Spectrum of Oxidatively Modified Serum Proteins Detected by Proteomics and Redox Proteomics Analysis

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system. Several evidences suggest that MS can be considered a multi-factorial disease in which both genetics and environmental factors are involved. Among proposed candidates, growing results support the involvement of oxidative stress (OS) in MS pathology. The aim of this study was to investigate the role of OS in event of exacerbations in MS on serum of relapsing-remitting (RR-MS) patients, either in relapsing or remitting phase, with respect to serum from healthy subjects. We applied proteomics and redox proteomics approaches to identify differently expressed and oxidatively modified proteins in the low-abundant serum protein fraction. Among differently expressed proteins ceruloplasmin, antithrombin III, clusterin, apolipoprotein E, and complement C3, were up-regulated in MS patients compared with healthy controls. Further by redox proteomics, vitamin D-binding protein showed a progressive trend of oxidation from remission to relapse, respect with controls. Similarly, the increase of oxidation of apolipoprotein A-IV confirmed that levels of OS are elevated with the progression of the disease. Our findings support the involvement of OS in MS and suggest that dysfunction of target proteins occurs upon oxidative damage and correlates with the pathology.

多发性硬化（Multiple sclerosis, MS）是一种累及中枢神经系统的自身免疫性炎性脱髓鞘疾病。现有多项证据表明，MS属于多因素疾病，其发生发展同时受遗传与环境因素共同调控。在诸多候选致病机制中，越来越多的研究结果支持氧化应激（oxidative stress, OS）参与了MS的病理进程。本研究旨在探究氧化应激在复发缓解型多发性硬化（relapsing-remitting, RR-MS）患者急性发作期与缓解期血清中的作用，并以健康受试者血清作为对照。研究采用蛋白质组学与氧化还原蛋白质组学技术，对低丰度血清蛋白组分中差异表达及氧化修饰的蛋白进行鉴定。相较于健康对照，MS患者血清中的差异表达蛋白包括铜蓝蛋白、抗凝血酶III、簇蛋白、载脂蛋白E及补体C3，上述蛋白均呈现上调表达。进一步通过氧化还原蛋白质组学分析发现，维生素D结合蛋白的氧化程度从缓解期到发作期呈进行性升高趋势，且显著高于健康对照。同样，载脂蛋白A-IV的氧化水平升高也证实，随着疾病进展，机体氧化应激水平显著提升。本研究结果证实氧化应激参与了MS的病理过程，并提示靶蛋白的氧化损伤所导致的功能异常与疾病病理密切相关。