@article{991db1e249c249aca3eae0dbcbbe8ca4,
title = "Arginine methyltransferase PRMT8 provides cellular stress tolerance in aging motoneurons",
abstract = "Aging contributes to cellular stress and neurodegeneration. Our understanding is limited regarding the tissue-restricted mechanisms providing protection in postmitotic cells throughout life. Here, we show that spinal cord motoneurons exhibit a high abundance of asymmetric dimethyl arginines (ADMAs) and the presence of this posttranslational modification provides protection against environmental stress. We identify protein arginine methyltransferase 8 (PRMT8) as a tissue-restricted enzyme responsible for proper ADMA level in postmitotic neurons. Male PRMT8 knock-out mice display decreased muscle strength with aging due to premature destabilization of neuromuscular junctions. Mechanistically, inhibition of methyltransferase activity or loss of PRMT8 results in accumulation of unrepaired DNA double-stranded breaks and decrease in the cAMP response-element-binding protein 1 (CREB1) level. As a consequence, the expression of CREB1-mediated prosurvival and regeneration-associated immediate early genes is dysregulated in aging PRMT8 knock-out mice. The uncovered role of PRMT8 represents a novel mechanism of stress tolerance in long-lived postmitotic neurons and identifies PRMT8 as a tissue-specific therapeutic target in the prevention of motoneuron degeneration.",
keywords = "ADMA, Aging, CREB1, Motoneuron, Neurodegeneration, PRMT8",
author = "Zoltan Simandi and Krisztian Pajer and Katalin Karolyi and Tatiana Sieler and Jiang, {Lu Lin} and Zsuzsanna Kolostyak and Zsanett Sari and Zoltan Fekecs and Attila Pap and Andreas Patsalos and Contreras, {Gerardo Alvarado} and Balint Reho and Zoltan Papp and Xiufang Guo and Attila Horvath and Greta Kiss and Zsolt Keresztessy and Gy{\"o}rgy V{\'a}mosi and James Hickman and Huaxi Xu and Dorothee Dormann and Tibor Hortobagyi and Miklos Antal and Antal N{\'o}gr{\'a}di and Laszlo Nagy",
note = "Funding Information: This work was supported by the research program GINOP-2.3.2-15/2016-00043 (T.H.), KTIA_13_NAP-A_II/7 (T.H.), GINOP 2.3.2-15-2016-00034 (A.N.), KTIA_NAP_13-1-2013-0001 (M.A.), and MTA-TKI 242 (M.A.). L.N. is supported by grants from the Hungarian Scientific Research Fund (OTKA 116855, 124298, 126885) and TAMOP 422_2012_0023 V{\'E}D-ELEM implemented through the New Hungary Development Plan cofinanced by the Euro-peanSocialFundandtheEuropeanRegionalDevelopmentFundandtheHungarianBrainResearchProgram(Grant KTIA_13_NAP-A-I/9).D.D.issupportedbytheDeutscheForschungsgemeinschaft,withintheframeworkofMunich ClusterSystemsNeurology(EXC1010SyNergy)andtheEmmyNoetherprogram(DO1804/1-1).H.X.issupportedby the National Institutes of Health (Grants R21 AG048519, R01 AG021173, R01 AG038710, R01 AG044420, R01 NS046673, RF1 AG056130, and RF1 AG056114), the Tanz Family Fund, and Cure Alzheimer{\textquoteright}s Fund. We thank Drs. RandyKaufman,BarbaraRanscht(SanfordBurnhamPrebysMedicalDiscoveryInstitute),PeterSomogyi(University ofOxford),andmembersoftheNagylaboratoryfordiscussionsandcommentsonthemanuscriptandMrs.HejaAga and Dr. Andras Szabo for technical assistance with imunohistochemistry. The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2018 the authors.",
year = "2018",
month = aug,
day = "29",
doi = "10.1523/JNEUROSCI.3389-17.2018",
language = "English (US)",
volume = "38",
pages = "7683--7700",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "35",
}