Lereim Ragnhild Reehorst, Oveland Eystein, Xiao Yichuan, Torkildsen Øivind, Wergeland Stig, Myhr Kjell-Morten, Sun Shao-Cong, Berven Frode S
Proteomics Unit, Department of Biomedicine, University of Bergen, Norway; Kristian Gerhard Jebsen MS Research Centre, Department of Clinical Medicine, University of Bergen, Bergen Norway.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University, Shanghai 200031, China.
J Proteomics Bioinform. 2016 Sep;9(9):209-219. doi: 10.4172/jpb.1000408. Epub 2016 Sep 12.
The ubiquitin ligase has previously been suggested as a potential treatment target in multiple sclerosis. In the multiple sclerosis disease model, experimental autoimmune encephalomyelitis, knock-out led to less activated microglia and less inflammation in the central nervous system. Despite being important in microglia, expression has also been detected in glial and neuronal cells. In the present study the overall brain proteomes of knock-out mice and wild-type mice were compared prior to experimental autoimmune encephalomyelitis induction, at onset of the disease and at disease peak. Brain samples from the frontal hemisphere, peripheral from the extensive inflammatory foci, were analyzed using TMT-labeling of sample pools, and the discovered proteins were verified in individual mice using label-free proteomics. The greatest proteomic differences between knock-out and wild-type mice were observed at the disease peak. In knock-out a higher degree of antigen presentation, increased activity of adaptive and innate immune cells and alterations to proteins involved in iron metabolism were observed during experimental autoimmune encephalomyelitis. These results unravel global effects to the brain proteome when abrogating expression, underlining the importance of as a regulator of the immune response also peripheral to inflammatory foci during experimental autoimmune encephalomyelitis. The proteomics data is available in PRIDE with accession PXD003710.
泛素连接酶此前已被认为是多发性硬化症的一个潜在治疗靶点。在多发性硬化症疾病模型实验性自身免疫性脑脊髓炎中，敲除该酶会导致中枢神经系统中活化的小胶质细胞减少以及炎症减轻。尽管它在小胶质细胞中很重要，但在神经胶质细胞和神经元细胞中也检测到了其表达。在本研究中，对敲除小鼠和野生型小鼠在实验性自身免疫性脑脊髓炎诱导前、疾病发作时和疾病高峰期的全脑蛋白质组进行了比较。使用样本池的TMT标记分析了来自额叶半球、远离广泛炎症病灶的外周脑样本，并使用无标记蛋白质组学在个体小鼠中对发现的蛋白质进行了验证。在疾病高峰期观察到敲除小鼠和野生型小鼠之间最大的蛋白质组差异。在实验性自身免疫性脑脊髓炎期间，敲除小鼠中观察到更高程度的抗原呈递、适应性和先天性免疫细胞活性增加以及铁代谢相关蛋白质的改变。这些结果揭示了在敲除该酶表达时对脑蛋白质组的整体影响，强调了其作为实验性自身免疫性脑脊髓炎期间炎症病灶外周免疫反应调节因子的重要性。蛋白质组学数据可在PRIDE中获取，登录号为PXD003710。
