TY - JOUR
T1 - Increase of arginine dimethylation correlates with the progression and prognosis of ALS
AU - Ikenaka, Kensuke
AU - Atsuta, Naoki
AU - Maeda, Yasuhiro
AU - Hotta, Yuji
AU - Nakamura, Ryoichi
AU - Kawai, Kaori
AU - Yokoi, Daichi
AU - Hirakawa, Akihiro
AU - Taniguchi, Akira
AU - Morita, Mitsuya
AU - Mizoguchi, Kouichi
AU - Mochizuki, Hideki
AU - Kimura, K.
AU - Katsuno, Masahisa
AU - Sobue, Gen
N1 - Funding Information:
This work was supported by grants (15Aek0109071h0002 and 17ek0109284h0001) from the Japan Agency for Medical Research and Development, and the Health and Labor Sciences Research grant (H26-086), and Grants-in Aid (25461277 and 17K09778) for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan. A section of this study is the result of the Integrated Research on Neuropsychiatric Disorders study, which was performed under the Strategic Research Program for Brain Sciences by MEXT, Japan.
Publisher Copyright:
© American Academy of Neurology.
PY - 2019/4/16
Y1 - 2019/4/16
N2 - ObjectiveTo investigate whether arginine methylation is altered in patients with amyotrophic lateral sclerosis (ALS) and how it affects disease severity, progression, and prognosis.MethodsWe 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.ResultsThe 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.ConclusionThere was an enhancement of arginine dimethylation in patients with ALS, and the ADMA/l-Arginine ratio predicted disease progression and prognosis in such patients.
AB - ObjectiveTo investigate whether arginine methylation is altered in patients with amyotrophic lateral sclerosis (ALS) and how it affects disease severity, progression, and prognosis.MethodsWe 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.ResultsThe 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.ConclusionThere was an enhancement of arginine dimethylation in patients with ALS, and the ADMA/l-Arginine ratio predicted disease progression and prognosis in such patients.
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U2 - 10.1212/WNL.0000000000007311
DO - 10.1212/WNL.0000000000007311
M3 - Article
C2 - 30867270
AN - SCOPUS:85063651285
VL - 92
SP - E1868-E1877
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 16
ER -