A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation.
A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation.
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非受体酪氨酸激酶 Abl2/Arg 在实验性神经炎症中的作用。
DOI：
10.1007/s11481-018-9783-8
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Andersson,Åsa
中科院分区：
文献类型：
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作者：
Jacobsen,FrejaAksel;Scherer,AlexanderN;Mouritsen,Jeppe;Bragadóttir,Hera;ThomasBäckström,B;Sardar,Samra;Holmberg,Dan;Koleske,AnthonyJ;Andersson,Åsa
多发性硬化症是一种神经炎性退行性疾病，由活化的免疫细胞浸润中枢神经系统引起。疾病病因涉及遗传和环境因素。研究了与多发性硬化症实验性自身免疫性脑脊髓炎（EAE）模型中疾病发展相关的小鼠遗传位点Eae 27，以确定多发性硬化症的疾病易感因素和潜在药物靶点。对Eae 27同源系小鼠的研究表明，Eae 27内的遗传变异影响EAE的发生。Eae 2基因位于4.1兆碱基对长的Eae 27区域，编码非受体酪氨酸激酶Arg。Arg蛋白在细胞调节中起重要作用，此外，还参与通过B-和T-细胞受体的信号传导，这对于自身免疫应答很重要。单核苷酸多态性的存在导致精氨酸的近肌动蛋白相互作用结构域的氨基酸变化，除了改变淋巴细胞活化的同类小鼠免疫后与髓鞘抗原，makese 2/Arga EAE的候选基因。在这里，我们表明，非同义SNP不改变精氨酸的F-肌动蛋白的结合亲和力，但建议的作用，Abl激酶在中枢神经系统炎症发病机制，显示药理学抑制Abl激酶改善EAE，但不实验性关节炎。
Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus,Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of anEae27congenic mouse strain, revealed that genetic variation withinEae27influences EAE development. TheAbl2gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair longEae27region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makesAbl2/Arga candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg’s binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis.