Department of Neurology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Functional Genomics Center Zurich, University of Zurich/ETH Zurich, Zurich, Switzerland.
J Sleep Res. 2019 Jun;28(3):e12721. doi: 10.1111/jsr.12721. Epub 2018 Jul 1.
Fatigue in multiple sclerosis is a very common and cumbersome symptom, but its aetiology is poorly understood. Proteomics is increasingly implemented in multiple sclerosis research, but has not yet been used to study the neurobiological basis of fatigue in multiple sclerosis. To identify potential cerebrospinal fluid biomarkers of fatigue in multiple sclerosis, we collected cerebrospinal fluid of 20 patients with multiple sclerosis with fatigue (MS+), 20 patients with multiple sclerosis without fatigue (MS-), and 20 control subjects without multiple sclerosis and without fatigue (HC). We used a shotgun proteomics approach and label-free quantitative proteomics to analyse the protein content in cerebrospinal fluid. Selected proteins with differential abundance were further validated by immunoblotting. Out of 591 detected cerebrospinal fluid proteins, the abundance of nine proteins differed between the three groups, and seven additional proteins differed between MS+ and MS- patients. Using immunoblot or slot-blot techniques, we confirmed decreased levels of protein kinase C-binding protein NELL2, neural cell adhesion molecule L1-like protein, and reelin in MS+ patients. In conclusion, cerebrospinal fluid proteomics may provide insight into the neurobiological basis of fatigue in multiple sclerosis. The proteins identified to be decreased in MS+ are involved in synaptic plasticity and energy homeostasis, and thus appear as plausible biomarkers of this common symptom.
多发性硬化症中的疲劳是一种非常常见且令人困扰的症状，但它的病因尚未被充分理解。蛋白质组学在多发性硬化症研究中得到了越来越多的应用，但尚未用于研究多发性硬化症疲劳的神经生物学基础。为了确定多发性硬化症疲劳的潜在脑脊液生物标志物，我们收集了 20 例伴有疲劳的多发性硬化症患者（MS+）、20 例不伴有疲劳的多发性硬化症患者（MS-）和 20 例无多发性硬化症且不伴有疲劳的对照受试者（HC）的脑脊液。我们使用 shotgun 蛋白质组学方法和无标记定量蛋白质组学分析脑脊液中的蛋白质含量。通过免疫印迹进一步验证具有差异丰度的选定蛋白质。在检测到的 591 种脑脊液蛋白质中，有 9 种蛋白质在三组之间的丰度存在差异，另外 7 种蛋白质在 MS+和 MS-患者之间存在差异。使用免疫印迹或狭缝印迹技术，我们证实了 MS+患者中蛋白激酶 C 结合蛋白 NELL2、神经细胞黏附分子 L1 样蛋白和 reelin 的水平降低。总之，脑脊液蛋白质组学可能为多发性硬化症疲劳的神经生物学基础提供深入了解。在 MS+中发现减少的蛋白质参与突触可塑性和能量稳态，因此它们似乎是这种常见症状的合理生物标志物。
