Acta Neuropathologica

, Volume 131, Issue 4, pp 587–604 | Cite as

Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS

  • Marc Suárez-Calvet
  • Manuela Neumann
  • Thomas Arzberger
  • Claudia Abou-Ajram
  • Eva Funk
  • Hannelore Hartmann
  • Dieter Edbauer
  • Elisabeth Kremmer
  • Christoph Göbl
  • Moritz Resch
  • Benjamin Bourgeois
  • Tobias Madl
  • Stefan Reber
  • Daniel Jutzi
  • Marc-David Ruepp
  • Ian R. A. Mackenzie
  • Olaf Ansorge
  • Dorothee Dormann
  • Christian Haass
Original Paper

Abstract

Deposition of the nuclear DNA/RNA-binding protein Fused in sarcoma (FUS) in cytosolic inclusions is a common hallmark of some cases of frontotemporal lobar degeneration (FTLD-FUS) and amyotrophic lateral sclerosis (ALS-FUS). Whether both diseases also share common pathological mechanisms is currently unclear. Based on our previous finding that FUS deposits are hypomethylated in FTLD-FUS but not in ALS-FUS, we have now investigated whether genetic or pharmacological inactivation of Protein arginine methyltransferase 1 (PRMT1) activity results in unmethylated FUS or in alternatively methylated forms of FUS. To do so, we generated FUS-specific monoclonal antibodies that specifically recognize unmethylated arginine (UMA), monomethylated arginine (MMA) or asymmetrically dimethylated arginine (ADMA). Loss of PRMT1 indeed not only results in an increase of UMA FUS and a decrease of ADMA FUS, but also in a significant increase of MMA FUS. Compared to ADMA FUS, UMA and MMA FUS exhibit much higher binding affinities to Transportin-1, the nuclear import receptor of FUS, as measured by pull-down assays and isothermal titration calorimetry. Moreover, we show that MMA FUS occurs exclusively in FTLD-FUS, but not in ALS-FUS. Our findings therefore provide additional evidence that FTLD-FUS and ALS-FUS are caused by distinct disease mechanisms although both share FUS deposits as a common denominator.

Keywords

Frontotemporal lobar degeneration (FTLD) Amyotrophic lateral sclerosis (ALS) Fused in sarcoma (FUS) Arginine methylation Neurodegeneration Protein arginine methyltransferase 1 (PRMT1) Transportin-1 

Notes

Acknowledgments

We thank Alice Suelzen for technical assistance. We thank H. Earl Ruley (Vanderbilt University School of Medicine; Nashville, TN, USA) for kind gift of mouse embryonic stem cells (mES) (PRMT1 knock-out and wild-type controls) and Elmar Wahle (Martin-Luther-Universität Halle-Wittenberg, Germany) for gift of reagents.

This work was supported by the European Research Council under the European Union’s Seventh Framework Program (FP7/2007–2013)/ERC Grant Agreement No. 321366-Amyloid (advanced grant to C.H.), the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy D.D., C.H.) and the Emmy Noether program DO 1804/1-1 (to D.D.), and the general legacy of Mrs. Ammer (to the Ludwig-Maximilians-University/the chair of C.H.) and the German Helmholtz Association (Grant VH-VI-510 to C.H. and M.N.; Grant W2/W3-036 to M.N.). M.S. was supported by a grant from the Fondo de Investigación Sanitaria (FI09/00732), Instituto Carlos III, Madrid, Spain. T.M. was supported by the Bavarian Ministry of Sciences, Research and the Arts (Bavarian Molecular Biosystems Research Network), the German Research Foundation (Emmy Noether program MA 5703/1-1), the Centre for Integrated Protein Science Munich (CIPSM), the President’s International Fellowship Initiative of CAS (No:2015VBB045), and the National Natural Science Foundation of China (No. 31450110423). We gratefully acknowledge the support of the NOMIS foundation (to M.D.R.), the Holcim Stiftung zur Föderung der wissenschaftlichen Fortbildung (to M.D.R.), and the Fondation Dufloteau (to M.D.R.).

Compliances with ethical standards

Conflict of interest

The authors disclose no conflicts of interest.

Supplementary material

401_2016_1544_MOESM1_ESM.eps (16.9 mb)
Supplementary material 1 (EPS 17351 kb) Supplementary Fig. 1 To verify specificity in mES cells, the UMA FUS (14G1) (a) and MMA FUS (15E11) (b) antibodies were pre-incubated with increasing concentrations of the three peptides used for immunization: UMA FUS473-503, MMA FUS473-503 and ADMA FUS473-503. Subsequently, immunoblots on mES cell lysates using the UMA FUS antibody or MMA FUS antibody not pre-preincubated with any peptide (first lane) or pre-incubated with increasing concentrations of each of the peptides (second to forth lane) were performed. The specific band recognized by the UMA and MMA FUS antibodies selectively disappeared when it was pre-incubated with the UMA FUS473-503 or MMA FUS473-503 peptide, respectively. Asterisks indicate unspecific bands
401_2016_1544_MOESM2_ESM.eps (1.9 mb)
Supplementary material 2 (EPS 1894 kb) Supplementary Fig. 2 Isothermal titration calorimetry (ITC) titrations of Transportin-1 with differentially arginine methylated synthetic FUS. A FUS peptide solution was titrated into a Transportin-1 solution and the heat release upon binding of the peptide to Transportin-1 was detected. From the heat release, the characteristic thermodynamic parameters of interactions in solution including binding affinity, enthalpy changes (ΔH), and entropy changes (ΔS) can be determined. Experimental calorimetric data of the binding of FUS473-503 (synthetic) to Transportin-1 is shown. The arginine methylation status is indicated. The experiment was carried out at 25 °C. Dilution heats measured by titrating FUS into the corresponding buffer were in the range of the heat effects observed at the end of the titration (data not shown) and were subtracted for the analysis
401_2016_1544_MOESM3_ESM.tif (16.9 mb)
Supplementary material 3 (TIFF 17265 kb) Supplementary Fig. 3 (a) siRNAs against FUS, EWS, TAF-15 or a non-targeting control were transfected into HeLa cells, and cells were either left untreated or treated with AdOx. Lysates were analysed 48 h post-transfection by immunoblotting with the antibody raised against UMA FUS (2A3). This antibody only reacts with lysates derived from AdOx-treated cells and the signal disappears upon knockdown of FUS. Tubulin was used as a loading control and FUS, EWS and TAF-15 antibodies were used to examine knockdown efficiency. Immunohistochemical detection of UMA FUS in the superior frontal gyrus of a FTLD-FUS (NIFID) case using the 2A3 antibody. (b) In the FTLD-FUS case there are abundant neuronal cytoplasmic inclusions, which are not detectable in the frontal cortex of a control case (c). (d-f) Higher magnification reveals the diversity of NCI morphology as seen for 14G1 antibody (Fig. 9). Scale bars in b, c = 100 µm, scale bars in d-f = 50 µm
401_2016_1544_MOESM4_ESM.tif (16.9 mb)
Supplementary material 4 (TIFF 17346 kb) Supplementary Fig. 4 (a) siRNAs against FUS, EWS, TAF-15 or a non-targeting control were transfected into HeLa cells, and cells were either left untreated or treated with AdOx. Lysates were analysed 48 h post-transfection by immunoblotting with the antibody raised against MMA FUS (18E11). This antibody only reacts with lysates derived from AdOx-treated cells and the signal disappears upon knockdown of FUS. Tubulin was used as a loading control and FUS, EWS and TAF-15 antibodies were used to examine knockdown efficiency. Asterisks: unspecific bands. Immunohistochemical detection of MMA FUS in the superior frontal gyrus of a FTLD-FUS (NIFID) case using the 18E11 antibody. (b) In the FTLD-FUS case there are abundant neuronal cytoplasmic inclusions that are not detectable in the frontal cortex of a control case (c). (d-f) Higher magnification reveals the diversity of NCI morphology as seen for 15E11 antibody (Fig. 11). Scale bars in b, c = 100 µm, scale bars in d-f = 50 µm
401_2016_1544_MOESM5_ESM.tif (24.4 mb)
Supplementary material 5 (TIFF 25017 kb) Supplementary Fig. 5 Double immunofluorescence with the UMA FUS antibody 14G1 (a) or MMA FUS antibody 15E11 (b) (green), a TRN-specific antibody (red) and nuclear counterstaining with DAPI (blue) in a FTLD-FUS (NIFID) case. UMA FUS or MMA FUS-positive inclusions consistently showed co-labeling for TRN. Scale bar: 50 µm

References

  1. 1.
    Araya N, Hiraga H, Kako K, Arao Y, Kato S, Fukamizu A (2005) Transcriptional down-regulation through nuclear exclusion of EWS methylated by PRMT1. Biochem Biophys Res Commun 329:653–660. doi: 10.1016/j.bbrc.2005.02.018 CrossRefPubMedGoogle Scholar
  2. 2.
    Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, and why. Mol Cell 33:1–13. doi: 10.1016/j.molcel.2008.12.013 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Belyanskaya LL, Delattre O, Gehring H (2003) Expression and subcellular localization of Ewing sarcoma (EWS) protein is affected by the methylation process. Exp Cell Res 288:374–381CrossRefPubMedGoogle Scholar
  4. 4.
    Belyanskaya LL, Gehrig PM, Gehring H (2001) Exposure on cell surface and extensive arginine methylation of Ewing Sarcoma (EWS) protein. J Biol Chem 276:18681–18687. doi: 10.1074/jbc.M011446200 CrossRefPubMedGoogle Scholar
  5. 5.
    Brelstaff J, Lashley T, Holton JL, Lees AJ, Rossor MN, Bandopadhyay R, Revesz T (2011) Transportin1: a marker of FTLD-FUS. Acta Neuropathol 122:591–600. doi: 10.1007/s00401-011-0863-6 CrossRefPubMedGoogle Scholar
  6. 6.
    Chen DH, Wu KT, Hung CJ, Hsieh M, Li C (2004) Effects of adenosine dialdehyde treatment on in vitro and in vivo stable protein methylation in HeLa cells. J Biochem 136:371–376. doi: 10.1093/jb/mvh131 CrossRefPubMedGoogle Scholar
  7. 7.
    Chook YM, Süel KE (2011) Nuclear import by karyopherin-βs: recognition and inhibition. Biochim Biophys Acta 1813:1593–1606. doi: 10.1016/j.bbamcr.2010.10.014 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Deng Q, Holler CJ, Taylor G, Hudson KF, Watkins W, Gearing M, Ito D, Murray ME, Dickson DW, Seyfried NT, Kukar T (2014) FUS is phosphorylated by DNA-PK and accumulates in the cytoplasm after DNA damage. J Neurosci 34:7802–7813. doi: 10.1523/jneurosci.0172-14.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Dhar S, Vemulapalli V, Patananan AN, Huang GL, Di Lorenzo A, Richard S, Comb MJ, Guo A, Clarke SG, Bedford MT (2013) Loss of the major Type I arginine methyltransferase PRMT1 causes substrate scavenging by other PRMTs. Sci Rep 3:1311. doi: 10.1038/srep01311 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dickson DW (2001) Neuropathology of Pick’s disease. Neurology 56:S16–S20CrossRefPubMedGoogle Scholar
  11. 11.
    Dormann D, Capell A, Carlson AM, Shankaran SS, Rodde R, Neumann M, Kremmer E, Matsuwaki T, Yamanouchi K, Nishihara M, Haass C (2009) Proteolytic processing of TAR DNA binding protein-43 by caspases produces C-terminal fragments with disease defining properties independent of progranulin. J Neurochem 110:1082–1094. doi: 10.1111/j.1471-4159.2009.06211.x CrossRefPubMedGoogle Scholar
  12. 12.
    Dormann D, Haass C (2013) Fused in sarcoma (FUS): an oncogene goes awry in neurodegeneration. Mol Cell Neurosci 56:475–486. doi: 10.1016/j.mcn.2013.03.006 CrossRefPubMedGoogle Scholar
  13. 13.
    Dormann D, Madl T, Valori CF, Bentmann E, Tahirovic S, Abou-Ajram C, Kremmer E, Ansorge O, Mackenzie IR, Neumann M, Haass C (2012) Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J 31:4258–4275. doi: 10.1038/emboj.2012.261 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, Than ME, Mackenzie IR, Capell A, Schmid B, Neumann M, Haass C (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29:2841–2857. doi: 10.1038/emboj.2010.143 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gardiner M, Toth R, Vandermoere F, Morrice NA, Rouse J (2008) Identification and characterization of FUS/TLS as a new target of ATM. Biochem J 415:297–307. doi: 10.1042/BJ20081135 CrossRefPubMedGoogle Scholar
  16. 16.
    Guo A, Gu H, Zhou J, Mulhern D, Wang Y, Lee KA, Yang V, Aguiar M, Kornhauser J, Jia X, Ren J, Beausoleil SA, Silva JC, Vemulapalli V, Bedford MT, Comb MJ (2014) Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol Cell Proteomics 13:372–387. doi: 10.1074/mcp.O113.027870 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Holm IE, Englund E, Mackenzie IR, Johannsen P, Isaacs AM (2007) A reassessment of the neuropathology of frontotemporal dementia linked to chromosome 3. J Neuropathol Exp Neurol 66:884–891. doi: 10.1097/nen.0b013e3181567f02 CrossRefPubMedGoogle Scholar
  18. 18.
    Holm IE, Isaacs AM, Mackenzie IR (2009) Absence of FUS-immunoreactive pathology in frontotemporal dementia linked to chromosome 3 (FTD-3) caused by mutation in the CHMP2B gene. Acta Neuropathol 118:719–720. doi: 10.1007/s00401-009-0593-1 CrossRefPubMedGoogle Scholar
  19. 19.
    Hung CJ, Lee YJ, Chen DH, Li C (2009) Proteomic analysis of methylarginine-containing proteins in HeLa cells by two-dimensional gel electrophoresis and immunoblotting with a methylarginine-specific antibody. Protein J 28:139–147. doi: 10.1007/s10930-009-9174-3 CrossRefPubMedGoogle Scholar
  20. 20.
    Ito D, Seki M, Tsunoda Y, Uchiyama H, Suzuki N (2011) Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. Ann Neurol 69:152–162. doi: 10.1002/ana.22246 CrossRefPubMedGoogle Scholar
  21. 21.
    Jobert L, Argentini M, Tora L (2009) PRMT1 mediated methylation of TAF15 is required for its positive gene regulatory function. Exp Cell Res 315:1273–1286. doi: 10.1016/j.yexcr.2008.12.008 CrossRefPubMedGoogle Scholar
  22. 22.
    Kino Y, Washizu C, Aquilanti E, Okuno M, Kurosawa M, Yamada M, Doi H, Nukina N (2011) Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. Nucleic Acids Res 39:2781–2798. doi: 10.1093/nar/gkq1162 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Klevernic IV, Morton S, Davis RJ, Cohen P (2009) Phosphorylation of Ewing’s sarcoma protein (EWS) and EWS-Fli1 in response to DNA damage. Biochem J 418:625–634. doi: 10.1042/BJ20082097 CrossRefPubMedGoogle Scholar
  24. 24.
    Kwiatkowski TJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208. doi: 10.1126/science.1166066 CrossRefPubMedGoogle Scholar
  25. 25.
    Van Langenhove T, van der Zee J, Sleegers K, Engelborghs S, Vandenberghe R, Gijselinck I, Van den Broeck M, Mattheijssens M, Peeters K, De Deyn PP, Cruts M, Van Broeckhoven C (2010) Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 74:366–371. doi: 10.1212/WNL.0b013e3181ccc732 CrossRefPubMedGoogle Scholar
  26. 26.
    Lee HJ, Kim S, Pelletier J, Kim J (2004) Stimulation of hTAFII68 (NTD)-mediated transactivation by v-Src. FEBS Lett 564:188–198. doi: 10.1016/S0014-5793(04)00314-X CrossRefPubMedGoogle Scholar
  27. 27.
    Lee JM, Lee JS, Kim H, Kim K, Park H, Kim JY, Lee SH, Kim IS, Kim J, Lee M, Chung CH, Seo SB, Yoon JB, Ko E, Noh DY, Kim KI, Kim KK, Baek SH (2012) EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell 48:572–586. doi: 10.1016/j.molcel.2012.09.004 CrossRefPubMedGoogle Scholar
  28. 28.
    Leemann-Zakaryan RP, Pahlich S, Grossenbacher D, Gehring H (2011) Tyrosine phosphorylation in the C-terminal nuclear localization and retention signal (C-NLS) of the EWS protein. Sarcoma 2011:218483. doi: 10.1155/2011/218483 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Liu Q, Dreyfuss G (1995) In vivo and in vitro arginine methylation of RNA-binding proteins. Mol Cell Biol 15:2800–2808CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DM (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4. doi: 10.1007/s00401-009-0612-2 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Mackenzie IR, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9:995–1007. doi: 10.1016/S1474-4422(10)70195-2 CrossRefPubMedGoogle Scholar
  32. 32.
    Munoz DG, Neumann M, Kusaka H, Yokota O, Ishihara K, Terada S, Kuroda S, Mackenzie IR (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627. doi: 10.1007/s00401-009-0598-9 CrossRefPubMedGoogle Scholar
  33. 33.
    Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554CrossRefPubMedGoogle Scholar
  34. 34.
    Neumann M, Bentmann E, Dormann D, Jawaid A, DeJesus-Hernandez M, Ansorge O, Roeber S, Kretzschmar HA, Munoz DG, Kusaka H, Yokota O, Ang LC, Bilbao J, Rademakers R, Haass C, Mackenzie IR (2011) FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain 134:2595–2609. doi: 10.1093/brain/awr201 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931. doi: 10.1093/brain/awp214 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IR (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616. doi: 10.1007/s00401-009-0581-5 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. doi: 10.1126/science.1134108 CrossRefPubMedGoogle Scholar
  38. 38.
    Neumann M, Valori CF, Ansorge O, Kretzschmar HA, Munoz DG, Kusaka H, Yokota O, Ishihara K, Ang LC, Bilbao JM, Mackenzie IR (2012) Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations. Acta Neuropathol 124:705–716. doi: 10.1007/s00401-012-1020-6 CrossRefPubMedGoogle Scholar
  39. 39.
    Niu C, Zhang J, Gao F, Yang L, Jia M, Zhu H, Gong W (2012) FUS-NLS/Transportin 1 complex structure provides insights into the nuclear targeting mechanism of FUS and the implications in ALS. PLoS One 7:e47056. doi: 10.1371/journal.pone.0047056 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ong SE, Mittler G, Mann M (2004) Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nat Methods 1:119–126. doi: 10.1038/nmeth715 CrossRefPubMedGoogle Scholar
  41. 41.
    Orozco D, Tahirovic S, Rentzsch K, Schwenk BM, Haass C, Edbauer D (2012) Loss of fused in sarcoma (FUS) promotes pathological Tau splicing. EMBO Rep 13:759–764. doi: 10.1038/embor.2012.90 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Ostareck-Lederer A, Ostareck DH, Rucknagel KP, Schierhorn A, Moritz B, Huttelmaier S, Flach N, Handoko L, Wahle E (2006) Asymmetric arginine dimethylation of heterogeneous nuclear ribonucleoprotein K by protein-arginine methyltransferase 1 inhibits its interaction with c-Src. J Biol Chem 281:11115–11125. doi: 10.1074/jbc.M513053200 CrossRefPubMedGoogle Scholar
  43. 43.
    Pahlich S, Bschir K, Chiavi C, Belyanskaya L, Gehring H (2005) Different methylation characteristics of protein arginine methyltransferase 1 and 3 toward the Ewing Sarcoma protein and a peptide. Proteins 61:164–175. doi: 10.1002/prot.20579 CrossRefPubMedGoogle Scholar
  44. 44.
    Pawlak MR, Scherer CA, Chen J, Roshon MJ, Ruley HE (2000) Arginine N-methyltransferase 1 is required for early postimplantation mouse development, but cells deficient in the enzyme are viable. Mol Cell Biol 20:4859–4869. doi: 10.1128/MCB.20.13.4859-4869.2000 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Perreault A, Lemieux C, Bachand F (2007) Regulation of the nuclear poly(A)-binding protein by arginine methylation in fission yeast. J Biol Chem 282:7552–7562. doi: 10.1074/jbc.M610512200 CrossRefPubMedGoogle Scholar
  46. 46.
    Rappsilber J, Friesen WJ, Paushkin S, Dreyfuss G, Mann M (2003) Detection of arginine dimethylated peptides by parallel precursor ion scanning mass spectrometry in positive ion mode. Anal Chem 75:3107–3114CrossRefPubMedGoogle Scholar
  47. 47.
    Ravenscroft TA, Baker MC, Rutherford NJ, Neumann M, Mackenzie IR, Josephs KA, Boeve BF, Petersen R, Halliday GM, Kril J, van Swieten JC, Seeley WW, Dickson DW, Rademakers R (2013) Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS. Neurobiol Aging 34:2235.e11–2235.e13. doi: 10.1016/j.neurobiolaging.2013.04.004
  48. 48.
    Sylvestersen KB, Horn H, Jungmichel S, Jensen LJ, Nielsen ML (2014) Proteomic analysis of arginine methylation sites in human cells reveals dynamic regulation during transcriptional arrest. Mol Cell Proteomics 13:2072–2088. doi: 10.1074/mcp.O113.032748 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Talbot K, Ansorge O (2006) Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease. Hum Mol Genet 15:R182–R187. doi: 10.1093/hmg/ddl202 CrossRefPubMedGoogle Scholar
  50. 50.
    Tang J, Frankel A, Cook RJ, Kim S, Paik K, Williams KR, Clarke S, Herschman HR (2000) PRMT1 is the predominant type I protein arginine methyltransferase in mammalian cells. J Biol Chem 275:7723–7730CrossRefPubMedGoogle Scholar
  51. 51.
    Thandapani P, O’Connor TR, Bailey TL, Richard S (2013) Defining the RGG/RG motif. Mol Cell 50:613–623. doi: 10.1016/j.molcel.2013.05.021 CrossRefPubMedGoogle Scholar
  52. 52.
    Tradewell ML, Yu Z, Tibshirani M, Boulanger MC, Durham HD, Richard S (2012) Arginine methylation by PRMT1 regulates nuclear-cytoplasmic localization and toxicity of FUS/TLS harbouring ALS-linked mutations. Hum Mol Genet 21:136–149. doi: 10.1093/hmg/ddr448 CrossRefPubMedGoogle Scholar
  53. 53.
    Troakes C, Hortobágyi T, Vance C, Al-Sarraj S, Rogelj B, Shaw CE (2013) Transportin 1 colocalization with Fused in Sarcoma (FUS) inclusions is not characteristic for amyotrophic lateral sclerosis-FUS confirming disrupted nuclear import of mutant FUS and distinguishing it from frontotemporal lobar degeneration with FUS inclusi. Neuropathol Appl Neurobiol 39:553–561. doi: 10.1111/j.1365-2990.2012.01300.x CrossRefPubMedGoogle Scholar
  54. 54.
    Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211. doi: 10.1126/science.1165942 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Vance C, Scotter EL, Nishimura AL, Troakes C, Mitchell JC, Kathe C, Urwin H, Manser C, Miller CC, Hortobágyi T, Dragunow M, Rogelj B, Shaw CE (2013) ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules. Hum Mol Genet 22:2676–2688. doi: 10.1093/hmg/ddt117 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Yamaguchi A, Kitajo K (2012) The effect of PRMT1-mediated arginine methylation on the subcellular localization, stress granules, and detergent-insoluble aggregates of FUS/TLS. PLoS One 7:e49267. doi: 10.1371/journal.pone.0049267 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yang Y, Bedford MT (2013) Protein arginine methyltransferases and cancer. Nat Rev Cancer 13:37–50. doi: 10.1038/nrc3409 CrossRefPubMedGoogle Scholar
  58. 58.
    Yu MC, Bachand F, McBride AE, Komili S, Casolari JM, Silver PA (2004) Arginine methyltransferase affects interactions and recruitment of mRNA processing and export factors. Genes Dev 18:2024–2035. doi: 10.1101/gad.1223204 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Zhang ZC, Chook YM (2012) Structural and energetic basis of ALS-causing mutations in the atypical proline-tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS). Proc Natl Acad Sci 109:12017–12021. doi: 10.1073/pnas.1207247109 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Zurita-Lopez CI, Sandberg T, Kelly R, Clarke SG (2012) Human protein arginine methyltransferase 7 (PRMT7) is a type III enzyme forming ω-NG-monomethylated arginine residues. J Biol Chem 287:7859–7870. doi: 10.1074/jbc.M111.336271 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Marc Suárez-Calvet
    • 1
    • 7
    • 9
  • Manuela Neumann
    • 3
    • 4
  • Thomas Arzberger
    • 5
    • 6
    • 7
  • Claudia Abou-Ajram
    • 1
    • 2
  • Eva Funk
    • 1
  • Hannelore Hartmann
    • 7
    • 8
  • Dieter Edbauer
    • 7
    • 8
  • Elisabeth Kremmer
    • 10
  • Christoph Göbl
    • 11
    • 12
  • Moritz Resch
    • 11
    • 12
  • Benjamin Bourgeois
    • 11
    • 12
  • Tobias Madl
    • 11
    • 12
    • 13
    • 14
  • Stefan Reber
    • 15
    • 16
  • Daniel Jutzi
    • 15
  • Marc-David Ruepp
    • 15
  • Ian R. A. Mackenzie
    • 17
  • Olaf Ansorge
    • 18
  • Dorothee Dormann
    • 1
    • 2
    • 8
  • Christian Haass
    • 1
    • 7
    • 8
  1. 1.Biomedical Center (BMC), BiochemistryLudwig-Maximilians-University MunichMunichGermany
  2. 2.BioMedical Center (BMC), Lehrstuhl Zellbiologie (Anatomie III)Planegg-MartinsriedGermany
  3. 3.Department of NeuropathologyUniversity of TübingenTübingenGermany
  4. 4.DZNE, German Center for Neurodegenerative DiseasesTübingenGermany
  5. 5.Department of Psychiatry and PsychotherapyLudwig-Maximilians-University MunichMunichGermany
  6. 6.Center for Neuropathology and Prion ResearchLudwig-Maximilians-University MunichMunichGermany
  7. 7.German Center for Neurodegenerative Diseases (DZNE) MunichMunichGermany
  8. 8.Munich Cluster for Systems Neurology (SyNergy)MunichGermany
  9. 9.Universitat Autònoma de BarcelonaBellaterraSpain
  10. 10.Institute of Molecular ImmunologyHelmholtz Zentrum München, German Research Center for Environmental Health (GmbH)MunichGermany
  11. 11.Department of ChemistryCenter for Integrated Protein Science Munich (CIPSM), Technische Universität MünchenGarchingGermany
  12. 12.Institute of Structural Biology, Helmholtz Zentrum MünchenNeuherbergGermany
  13. 13.Institute of Molecular Biology and BiochemistryCenter of Molecular Medicine, Medical University of GrazGrazAustria
  14. 14.Omics Center Graz, BioTechMedGrazAustria
  15. 15.Department of Chemistry and BiochemistryUniversity of BernBernSwitzerland
  16. 16.Graduate School for Cellular and Biomedical Sciences, University of BernBernSwitzerland
  17. 17.Department of PathologyVancouver General Hospital, University of British ColumbiaVancouverCanada
  18. 18.Department of NeuropathologyJohn Radcliffe HospitalOxfordUK

Personalised recommendations