Citrullination of arginine residues is a post-translational modification (PTM) found on myelin basic protein (MBP), which neutralizes MBPs positive charge, and is implicated in myelin damage and multiple sclerosis (MS). Here we identify lysine acetylation as another neutralizing PTM to MBP that may be involved in myelin damage. We quantify changes in lysine and arginine PTMs on MBP derived from mice induced with an experimental autoimmune encephalomyelitis (EAE) model of MS using liquid chromatography tandem mass spectrometry. The changes in PTMs are correlated to changes in neurological disability scoring (NDS), as a marker of myelin damage. We found that lysine acetylation increased by two-fold on MBP during peak NDS post-EAE induction. We also found that, mono- and dimethyl-lysine, as well as asymmetric dimethyl-arginine residues on MBP were elevated at peak EAE disability. These findings suggest that the acetylation and methylation of lysine on MBP are PTMs associated with the neurological disability produced by EAE. Since histone deacetylase (HDAC) inhibitors have been previously shown to improve neurological disability, we also show that treatment with trichostatin A (a HDAC inhibitor) improves the NDS of EAE mice but does not change MBP acetylation.

中文翻译：

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髓鞘碱性蛋白的翻译后赖氨酸乙酰化增加与多发性硬化症的小鼠实验性自身免疫性脑脊髓炎模型的峰值神经功能障碍有关。

精氨酸残基的瓜氨酸化是在髓磷脂碱性蛋白（MBP）上发现的翻译后修饰（PTM），其中和MBPs的正电荷，并涉及髓磷脂损伤和多发性硬化症（MS）。在这里，我们确定赖氨酸乙酰化是MBP的另一种中和PTM，可能与髓磷脂的损伤有关。我们用液相色谱串联质谱法对MS的实验性自身免疫性脑脊髓炎（EAE）模型诱导的小鼠的MBP上的赖氨酸和精氨酸PTM的变化进行了定量分析。PTM的变化与神经功能障碍评分（NDS）的变化相关，后者是髓鞘损伤的标志。我们发现在EAE诱导后的峰值NDS期间，MBP上的赖氨酸乙酰化增加了两倍。我们还发现，单赖氨酸和二甲基赖氨酸 MBP上的不对称二甲基精氨酸残基在EAE残疾峰值时升高。这些发现表明，MBP上赖氨酸的乙酰化和甲基化是与EAE引起的神经功能障碍相关的PTM。由于以前已经证明组蛋白脱乙酰基酶（HDAC）抑制剂可改善神经功能障碍，因此我们还表明用曲古抑菌素A（一种HDAC抑制剂）治疗可改善EAE小鼠的NDS，但不会改变MBP乙酰化。