Kensuke Ikenaka1, Naoki Atsuta1, Yasuhiro Maeda1, Yuji Hotta1, Ryoichi Nakamura1, Kaori Kawai1, Daichi Yokoi1, Akihiro Hirakawa1, Akira Taniguchi1, Mitsuya Morita1, Kouichi Mizoguchi1, Hideki Mochizuki1, Kazunori Kimura1, Masahisa Katsuno1, Gen Sobue2. 1. 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. 2. 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. sobueg@med.nagoya-u.ac.jp.
Abstract
OBJECTIVE: To investigate whether arginine methylation is altered in patients with amyotrophic lateral sclerosis (ALS) and how it affects disease severity, progression, and prognosis. METHODS: 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. RESULTS: The immunoreactivity of both PRMT1 (p < 0.0001) and ASYM (p = 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 (r = 0.406, p = 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. CONCLUSION: 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.
OBJECTIVE: To investigate whether arginine methylation is altered in patients with amyotrophic lateral sclerosis (ALS) and how it affects disease severity, progression, and prognosis. METHODS: 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. RESULTS: The immunoreactivity of both PRMT1 (p < 0.0001) and ASYM (p = 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 (r = 0.406, p = 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. CONCLUSION: 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.
Authors: Marie Dreger; Robert Steinbach; Markus Otto; Martin R Turner; Julian Grosskreutz Journal: J Neurol Neurosurg Psychiatry Date: 2022-02-01 Impact factor: 13.654