Increase of arginine dimethylation correlates with the progression and prognosis of ALS

Kensuke Ikenaka, Naoki Atsuta, Yasuhiro Maeda, Yuji Hotta, Ryoichi Nakamura, Kaori Kawai, Daichi Yokoi, Akihiro Hirakawa, Akira Taniguchi, Mitsuya Morita, Kouichi Mizoguchi, Hideki Mochizuki, Kazunori Kimura, Masahisa Katsuno, Gen Sobue

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Abstract

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.

Original languageEnglish
Pages (from-to)E1868-E1877
JournalNeurology
Volume92
Issue number16
DOIs
Publication statusPublished - 16-04-2019

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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    Ikenaka, K., Atsuta, N., Maeda, Y., Hotta, Y., Nakamura, R., Kawai, K., Yokoi, D., Hirakawa, A., Taniguchi, A., Morita, M., Mizoguchi, K., Mochizuki, H., Kimura, K., Katsuno, M., & Sobue, G. (2019). Increase of arginine dimethylation correlates with the progression and prognosis of ALS. Neurology, 92(16), E1868-E1877. https://doi.org/10.1212/WNL.0000000000007311