PT  - JOURNAL ARTICLE
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, Kazunori
AU  - Katsuno, Masahisa
AU  - Sobue, Gen
TI  - Increase of arginine dimethylation correlates with the progression and prognosis of ALS
AID  - 10.1212/WNL.0000000000007311
DP  - 2019 Apr 16
TA  - Neurology
PG  - e1868--e1877
VI  - 92
IP  - 16
4099  - http://n.neurology.org/content/92/16/e1868.short
4100  - http://n.neurology.org/content/92/16/e1868.full
SO  - Neurology2019 Apr 16; 92
AB  - 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.ADMA=asymmetric dimethyl l-arginine; ALS=amyotrophic lateral sclerosis; ALSFRS-R=ALS Functional Rating Scale; ASYM=asymmetric dimethylated proteins; CI=confidence interval; CK=creatinine kinase; HR=hazard ratio; MMT=Manual Muscle Testing; NMMA=NG-monomethyl l-arginine; %FVC=percentage forced vital capacity; PRMT=protein arginine methyltransferase; SDMA=symmetric dimethyl l-arginine; TPPV=tracheostomy positive pressure ventilation