From the Department of Neurology (K.I., N.A., R.N., K. Kawai, D.Y., M.K., G.S.), Nagoya University Graduate School of Medicine; Department of Neurology (K.I., H.M.), Osaka University Graduate School of Medicine, Suita; Department of Hospital Pharmacy (Y.M., Y.H., K. Kimura), Nagoya City University Graduate School of Pharmaceutical Sciences; Department of Biostatistics and Bioinformatics (A.H.), University of Tokyo; Department of Neurology (A.T.), Mie University Graduate School of Medicine, Tsu; Department of Neurology (M.M.), Jichi Medical University, Shimotsuke, Tochigi; National Hospital Organization, Shizuoka Medical Center (K.M.); and Brain and Mind Research Center (G.S.), Nagoya University, Aichi, Japan.
Neurology. 2019 Apr 16;92(16):e1868-e1877. doi: 10.1212/WNL.0000000000007311. Epub 2019 Mar 13.
To investigate whether arginine methylation is altered in patients with amyotrophic lateral sclerosis (ALS) and how it affects disease severity, progression, and prognosis.
We compared the immunoreactivity of protein arginine methyltransferase 1 (PRMT1) and its products, asymmetric dimethylated proteins (ASYM), in postmortem spinal cord. We also measured the concentrations of total l-arginine and methylated arginine residues, including asymmetric dimethyl l-arginine (ADMA), symmetric dimethyl arginine, and monomethyl arginine, in CSF samples from 52 patients with ALS using liquid chromatography-tandem mass spectrometry, and we examined their relationship with the progression and prognosis of ALS.
The immunoreactivity of both PRMT1 ( < 0.0001) and ASYM ( = 0.005) was increased in patients with ALS. The concentration of ADMA in CSF was substantially higher in patients with ALS than in disease controls. The ADMA/l-arginine ratio was correlated with the change of decline in the ALS Functional Rating Scale at 12 months after the time of measurement ( = 0.406, = 0.010). A Cox proportional hazards model showed that the ADMA/l-arginine ratio was an independent predictor for overall survival. Moreover, a high ADMA/l-arginine ratio predicted poor prognosis, even in a group with normal percentage forced vital capacity.
There was an enhancement of arginine dimethylation in patients with ALS, and the ADMA/l-arginine ratio predicted disease progression and prognosis in such patients.
探讨精氨酸甲基化在肌萎缩侧索硬化症（ALS）患者中是否发生改变，以及其如何影响疾病的严重程度、进展和预后。
我们比较了尸检脊髓中蛋白精氨酸甲基转移酶 1（PRMT1）及其产物不对称二甲基化蛋白（ASYM）的免疫反应性。我们还使用液相色谱-串联质谱法测量了 52 例 ALS 患者脑脊液样本中总 l-精氨酸和甲基化精氨酸残基（包括不对称二甲基 l-精氨酸（ADMA）、对称二甲基精氨酸和单甲基精氨酸）的浓度，并研究了它们与 ALS 进展和预后的关系。
PRMT1（<0.0001）和 ASYM（=0.005）的免疫反应性在 ALS 患者中均增加。与疾病对照组相比，ALS 患者的 CSF 中 ADMA 浓度明显更高。ADMA/精氨酸比值与测量后 12 个月 ALS 功能评定量表下降的变化相关（=0.406，=0.010）。Cox 比例风险模型显示 ADMA/精氨酸比值是总生存期的独立预测因子。此外，高 ADMA/精氨酸比值预示着预后不良，即使在正常肺活量百分比的患者中也是如此。
ALS 患者中存在精氨酸二甲基化增强，ADMA/精氨酸比值可预测此类患者的疾病进展和预后。
