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Arginine Methyltransferase PRMT8 Provides Cellular Stress Tolerance in Aging Motoneurons

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Arginine Methyltransferase PRMT8 Provides Cellular Stress Tolerance in Aging Motoneurons This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. A link to any extended data will be provided when the final version is posted online. Research Articles: Development/Plasticity/Repair Arginine methyltransferase PRMT8 provides cellular stress tolerance in aging motoneurons Zoltan Simandi1,2, Krisztian Pajer3, Katalin Karolyi1, Tatiana Sieler1, Lu-Lin Jiang4, Zsuzsanna Kolostyak2, Zsanett Sari2, Zoltan Fekecs3, Attila Pap2, Andreas Patsalos2, Gerardo Alvarado Contreras5, Balint Reho6, Zoltan Papp5, Xiufang Guo7, Attila Horvath2, Greta Kiss8, Zsolt Keresztessy2, György Vámosi6, James Hickman7, Huaxi Xu4, Dorothee Dormann9,10, Tibor Hortobagyi11, Miklos Antal8,12, Antal Nogradi3 and Laszlo Nagy1,2,13 1Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA, FL 32827 2Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, HU 4032 3Department of Anatomy, Histology and Embryology, University of Szeged, Szeged, Hungary, HU 6720 4Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA, CA 92037 5Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, HU 4032 6Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, HU 4032 7NanoScience Technology Center, University of Central Florida, Orlando, Florida, USA, FL 32816 8Department of Anatomy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, HU 4032 9BioMedical Center (BMC), Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany, 80539 10Munich Cluster for Systems Neurology (SyNergy), Munich, Germany, 80539 11MTA-DE Cerebrovascular and Neurodegenerative Research Group, Department of Neurology and Neuropathology, University of Debrecen, Debrecen, Hungary, HU 4032 12MTA-DE Neuroscience Research Group, University of Debrecen, Debrecen, Hungary, HU 4032 13MTA-DE “Lendulet” Immunogenomics Research Group, University of Debrecen, Debrecen, Hungary, HU 4032 DOI: 10.1523/JNEUROSCI.3389-17.2018 Received: 29 November 2017 Revised: 22 June 2018 Accepted: 25 June 2018 Published: 27 July 2018 Author contributions: Z. Simandi, K.P., and L.N. designed research; Z. Simandi, K.P., K.K., T.S., L.-L.J., Z. Kolostyak, Z. Sari, Z.F., A. Pap, A. Patsalos, G.A.C., B.R., X.G., and G.K. performed research; Z. Simandi, K.P., A.H., G.V., T.H., M.A., A.N., and L.N. analyzed data; Z. Simandi and L.N. edited the paper; Z. Simandi, A.N., and L.N. wrote the paper; Z.P., Z. Keresztessy, J.H., H.X., D.D., M.A., and A.N. contributed unpublished reagents/analytic tools. Conflict of Interest: The authors declare no competing financial interests. The authors would like to acknowledge Drs. Randy Kaufman, Barbara Ranscht (SBP), Peter Somogyi (University of Oxford) and members of the Nagy laboratory for discussions and comments on the manuscript and Dr. Andras Szabo (SBP) for technical assistance with imunohistochemistry. L.N is supported by grants from the Hungarian Scientific Research Fund (OTKA K100196, K111941 and K116855) and TAMOP 422_2012_0023 Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors VÉD-ELEM implemented through the New Hungary Development Plan co-financed by the European Social Fund and the European Regional Development Fund and the Hungarian Brain Research Program -- Grant No. KTIA_13_NAP-A-I/9. 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.), MTA- TKI 242 (M.A.). D.D. is supported by the Deutsche Forschungsgemeinschaft (DFG) within the framework of Munich Cluster Systems Neurology (EXC 1010 SyNergy) and the Emmy Noether program (DO 1804/1-1). H.X. is supported by grants from the NIH (R21 AG048519, R01 AG021173, R01 AG038710, R01 AG044420, R01 NS046673, RF1 AG056130 and RF1 AG056114), by the Tanz Family Fund and Cure Alzheimer's Fund. Correspondence information: Name: Laszlo Nagy, Address: 6400 Sanger Road, Orlando, FL 32827, Phone: +1-407-745-2150, E-mail: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.3389-17.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. 1 Title: Arginine methyltransferase PRMT8 provides cellular stress tolerance in aging 2 motoneurons 3 Abbreviated title: PRMT8 provides stress tolerance in neurons 4 5 Zoltan Simandi1,2, Krisztian Pajer3, Katalin Karolyi1, Tatiana Sieler1, Lu-Lin Jiang4, Zsuzsanna 6 Kolostyak2, Zsanett Sari2, Zoltan Fekecs3, Attila Pap2, Andreas Patsalos2, Gerardo Alvarado 7 Contreras5, Balint Reho6, Zoltan Papp5, Xiufang Guo7, Attila Horvath2, Greta Kiss8, Zsolt 8 Keresztessy2, György Vámosi6, James Hickman7, Huaxi Xu4, Dorothee Dormann,9,10, Tibor 9 Hortobagyi11, Miklos Antal8,12, Antal Nogradi3 and Laszlo Nagy1,2,13,# 10 11 1Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA, FL 32827 12 2Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of 13 Debrecen, Debrecen, Hungary, HU 4032 14 3Department of Anatomy, Histology and Embryology, University of Szeged, Szeged, Hungary, 15 HU 6720 16 4Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, 17 California, USA, CA 92037 18 5Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of 19 Debrecen, Debrecen, Hungary, HU 4032 20 6Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 21 Debrecen, Hungary, HU 4032 22 7NanoScience Technology Center, University of Central Florida, Orlando, Florida, USA, FL 23 32816 1 24 8Department of Anatomy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, HU 25 4032 26 9BioMedical Center (BMC), Ludwig-Maximilians-University Munich, Planegg-Martinsried, 27 Germany, 80539 28 10Munich Cluster for Systems Neurology (SyNergy), Munich, Germany, 80539 29 11MTA-DE Cerebrovascular and Neurodegenerative Research Group, Department of Neurology 30 and Neuropathology, University of Debrecen, Debrecen, Hungary, HU 4032 31 12MTA-DE Neuroscience Research Group, University of Debrecen, Debrecen, Hungary, HU 32 4032 33 13MTA-DE “Lendulet” Immunogenomics Research Group, University of Debrecen, Debrecen, 34 Hungary, HU 4032 35 36 #Correspondence information: 37 Name: Laszlo Nagy 38 Address: 6400 Sanger Road, Orlando, FL 32827 39 Phone: +1-407-745-2150 40 E-mail: [email protected] 41 42 2 43 Number of pages: 51 44 Number of Figures: 8 45 Number of words for Abstract: 158 46 Number of words for Introduction: 685 47 Number of words for Discussion: 1269 3 48 DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST 49 The authors have declared that no potential conflicts of interest exist. 50 51 4 52 ACKNOWLEDGEMENT 53 The authors would like to acknowledge Drs. Randy Kaufman, Barbara Ranscht (SBP), Peter 54 Somogyi (University of Oxford) and members of the Nagy laboratory for discussions and 55 comments on the manuscript and Dr. Andras Szabo (SBP) for technical assistance with 56 imunohistochemistry. L.N is supported by grants from the Hungarian Scientific Research Fund 57 (OTKA K100196, K111941 and K116855) and TAMOP 422_2012_0023 VÉD-ELEM 58 implemented through the New Hungary Development Plan co-financed by the European Social 59 Fund and the European Regional Development Fund and the Hungarian Brain Research Program 60 – Grant No. KTIA_13_NAP-A-I/9. This work was supported by the research program GINOP- 61 2.3.2-15/2016-00043 (T.H.), KTIA_13_NAP-A_II/7 (T.H.), GINOP 2.3.2-15-2016-00034 62 (A.N.), KTIA_NAP_13-1-2013-0001 (M.A.), MTA- TKI 242 (M.A.). D.D. is supported by the 63 Deutsche Forschungsgemeinschaft (DFG) within the framework of Munich Cluster Systems 64 Neurology (EXC 1010 SyNergy) and the Emmy Noether program (DO 1804/1-1). H.X. is 65 supported by grants from the NIH (R21 AG048519, R01 AG021173, R01 AG038710, R01 66 AG044420, R01 NS046673, RF1 AG056130 and RF1 AG056114), by the Tanz Family 67 Fund and Cure Alzheimer's Fund. 68 69 70 71 72 5 73 ABSTRACT 74 Aging contributes to cellular stress and neurodegeneration. Our understanding is limited 75 regarding the tissue-restricted mechanisms providing protection in post-mitotic cells throughout 76 life. Here, we show that spinal cord motoneurons exhibit a high abundance of asymmetric 77 dimethyl arginines (ADMA) and the presence of this posttranslational modification provides 78 protection against environmental stress. We identify Protein aRginine MethylTransferase 8 79 (PRMT8) as a tissue-restricted enzyme responsible for proper ADMA level in post-mitotic 80 neurons. Male PRMT8 knockout mice display decreased muscle strength with aging due to 81 premature destabilization of neuromuscular junctions. Mechanistically, inhibition of 82 methyltransferase activity or loss of PRMT8 results in accumulation of unrepaired DNA double- 83 stranded breaks and decrease in the CREB1 level. As a consequence, expression of CREB1- 84 mediated pro-survival and regeneration-associated immediate early genes are dysregulated in 85 aging PRMT8 knockout mice. The uncovered role of PRMT8 represents a novel mechanism of 86 stress tolerance in long-lived post-mitotic neurons and identifies PRMT8 as a tissue-specific 87 therapeutic target in the prevention of
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