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Abstract：
Friedreich\'s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded (GAA) trinucleotide repeat in the FXN gene. The extended repeats expansion results in reduced transcription and, thereby, decreased expression of the mitochondrial protein, frataxin. Given the ongoing drug trials, identification of reliable and easily accessible biomarkers for monitoring disease progression and therapeutic intervention is a foremost requirement. In this study, comparative proteomic profiling of PBMC proteins from FRDA patients and age- and gender-matched healthy controls was done using 2D-Differential in-Gel Electrophoresis (2D-DIGE). Protein-protein interaction (PPI) was analyzed using BioGRID and STRING pathway analysis tools. Using biological variance analysis (BVA) and LC/MS, we found eight differentially expressed proteins with fold change ≥1.5; p ≤ 0.05. Based on their cellular function, the identified proteins showed a strong pathological role in neuroinflammation, cardiomyopathy, compromised glucose metabolism, and iron transport, which are the major clinical manifestations of FRDA. Protein-protein network analysis of differentially expressed proteins with frataxin further supports their involvement in the pathophysiology of FRDA. Considering their crucial role in the cardiac and neurological complications, respectively, the two down-regulated proteins, actin α cardiac muscle 1 (ACTC1) and pyruvate dehydrogenase E1 component subunit β (PDHE1), are suggested as potential prognostic markers for FRDA.
摘要：
Friedreich共济失调（FRDA）是一种常染色体隐性遗传神经退行性疾病，由FXN基因中扩展的（GAA）三核苷酸重复序列引起。延伸的重复扩增导致转录减少，因此，线粒体蛋白表达降低，Frataxin.鉴于正在进行的药物试验,确定可靠且易于获取的生物标志物以监测疾病进展和治疗干预是最重要的要求.在这项研究中,使用2D-差异凝胶电泳(2D-DIGE)对FRDA患者和年龄和性别匹配的健康对照进行PBMC蛋白的比较蛋白质组学分析。使用BioGRID和STRING途径分析工具分析蛋白质-蛋白质相互作用(PPI)。采用生物方差分析(BVA)和LC/MS,我们发现八种差异表达的蛋白质，其倍数变化≥1.5；p≤0.05。基于它们的细胞功能,鉴定的蛋白质在神经炎症中表现出强烈的病理作用，心肌病,葡萄糖代谢受损，和铁运输，这是FRDA的主要临床表现。具有共济失调蛋白的差异表达蛋白质的蛋白质-蛋白质网络分析进一步支持它们参与FRDA的病理生理学。考虑到它们在心脏和神经系统并发症中的关键作用，分别,这两种下调的蛋白质，肌动蛋白α心肌1（ACTC1）和丙酮酸脱氢酶E1亚基β（PDHE1），被认为是FRDA的潜在预后标志物。
