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

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• 作者：Marc Suárez-Calvet ; Manuela Neumann ; Thomas Arzberger…
• 关键词：Frontotemporal lobar degeneration (FTLD) ; Amyotrophic lateral sclerosis (ALS) ; Fused in sarcoma (FUS) ; Arginine methylation ; Neurodegeneration ; Protein arginine methyltransferase 1 (PRMT1) ; Transportin ; 1
• 刊名：Acta Neuropathologica
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：131
• 期：4
• 页码：587-604
• 全文大小：4,237 KB
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• 作者单位：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. Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany
  7. German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany
  9. Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain
  3. Department of Neuropathology, University of Tübingen, 72076, Tübingen, Germany
  4. DZNE, German Center for Neurodegenerative Diseases, 72076, Tübingen, Germany
  5. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, 80336, Munich, Germany
  6. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
  2. BioMedical Center (BMC), Lehrstuhl Zellbiologie (Anatomie III), Großhaderner Strasse 9, 82152, Planegg-Martinsried, Germany
  8. Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany
  10. Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 81377, Munich, Germany
  11. Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstr.4, 85747, Garching, Germany
  12. Institute of Structural Biology, Helmholtz Zentrum München, 85764, Neuherberg, Germany
  13. Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010, Graz, Austria
  14. Omics Center Graz, BioTechMed, 8010, Graz, Austria
  15. Department of Chemistry and Biochemistry, University of Bern, 3012, Bern, Switzerland
  16. Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012, Bern, Switzerland
  17. Department of Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, Canada
  18. Department of Neuropathology, John Radcliffe Hospital, Oxford, UK
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pathology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0533

文摘

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.