SOD1D90A突变外泌体蛋白质组学提示疾病早期机制,FN1可作为生物标志物

IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY
Mukesh Gautam, Ali Laith, Aslihan Gunel, Melda Yilmaz, Nazli Basak, Halil Idrisoglu, P Hande Ozdinler
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引用次数: 0

摘要

肌萎缩侧索硬化症(ALS)是一种神经肌肉疾病。超氧化物歧化酶1 (SOD1)基因突变导致ALS, D90A突变主要与上运动神经元(UMN)丢失有关。目的:我们的目标是通过明确定义的患者群体,揭示ALS病理中的早期细胞事件,并确定潜在的药代动力学生物标志物。方法:从单个或多个时间点的SOD1D90A突变家族成员的血清中分离外泌体,采用串联质谱蛋白质组学方法测定其蛋白质含量。匠心途径分析用于强调随着疾病进展而受到干扰的细胞事件。线性回归分析,利用患者的ALSFRS评分和蛋白质含量,帮助确定潜在的药代动力学生物标志物,并通过ELISA试验证实。结果:父亲、儿子和女儿处于不同的疾病阶段,携带SOD1D90A突变。尽管女儿在一年内没有症状;她有明显的生理变化。圣子在一年内从无症状过渡到早期症状,而圣父则有症状。2号患者也有SOD1D90A突变,病情更严重。儿子、父亲和患者2号的比较表明,纤维连接蛋白1 (FN1)是一种潜在的药代动力学生物标志物,ELISA证实了这一点。解释:外泌体蛋白质组学提供了一种强大的方法来询问血液中存在的疾病特异性或疾病相关蛋白质。这有助于定义与疾病进展相关的扰动细胞事件,并揭示潜在的药代动力学生物标志物。我们发现FN1水平随着疾病进展而增加,这表明它可能是一种药代动力学生物标志物,特别是对于具有明显UMN丢失的ALS患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Exosome Proteomics of SOD1D90A Mutation Suggest Early Disease Mechanisms, and FN1 as a Biomarker.

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. Super oxide dismutase 1 (SOD1) gene mutations cause ALS, and the D90A mutation is associated with primarily upper motor neuron (UMN) loss.

Objective: Our goal is to reveal the early cellular events in ALS pathology and identify potential pharmacokinetic biomarkers, using well-defined patient populations.

Methods: Exosomes are isolated from serum either single or multiple time points from members of one family, who have SOD1D90A mutation, and their protein content is assessed by tandem mass-spec proteomics. Ingenuity Pathway analysis is used to highlight cellular events that are perturbed as the disease progressed. The linear regression analysis, using ALSFRS scores of patients and the protein content, helps identify potential pharmacokinetic biomarkers, which are confirmed with the ELISA assay.

Results: Father, Son, and Daughter are at different disease stages and carry the SOD1D90A mutation. Albeit, the Daughter remained asymptomatic within a year; she had significant biological changes. The Son transitioned from asymptomatic to early symptomatic within a year, while the Father was symptomatic. Patient #2, who also had the SOD1D90A mutation, was more advanced. Comparison of the Son, Father, and Patient #2 suggested Fibronectin1 (FN1) as a potential pharmacokinetic biomarker, which is confirmed by ELISA.

Interpretation: Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss.

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来源期刊
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)
CiteScore
9.10
自引率
1.90%
发文量
218
审稿时长
8 weeks
期刊介绍: Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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