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

  • Suárez-Calvet M Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany.
  • Neumann M Department of Neuropathology, University of Tübingen, 72076, Tübingen, Germany.
  • Arzberger T Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, 80336, Munich, Germany.
  • Abou-Ajram C Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany.
  • Funk E Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany.
  • Hartmann H German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany.
  • Edbauer D German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany.
  • Kremmer E Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 81377, Munich, Germany.
  • Göbl C Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstr.4, 85747, Garching, Germany.
  • Resch M Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstr.4, 85747, Garching, Germany.
  • Bourgeois B Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstr.4, 85747, Garching, Germany.
  • Madl T Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstr.4, 85747, Garching, Germany.
  • Reber S Department of Chemistry and Biochemistry, University of Bern, 3012, Bern, Switzerland.
  • Jutzi D Department of Chemistry and Biochemistry, University of Bern, 3012, Bern, Switzerland.
  • Ruepp MD Department of Chemistry and Biochemistry, University of Bern, 3012, Bern, Switzerland.
  • Mackenzie IR Department of Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, Canada.
  • Ansorge O Department of Neuropathology, John Radcliffe Hospital, Oxford, UK.
  • Dormann D Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany. dorothee.dormann@med.uni-muenchen.de.
  • Haass C Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.
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  • 2016-02-20
Published in:
  • Acta neuropathologica. - 2016
Amyotrophic lateral sclerosis (ALS)
Arginine methylation
Frontotemporal lobar degeneration (FTLD)
Fused in sarcoma (FUS)
Neurodegeneration
Protein arginine methyltransferase 1 (PRMT1)
Transportin-1
Amyotrophic Lateral Sclerosis
Animals
Antibodies
Arginine
Cells, Cultured
Cerebral Cortex
Embryo, Mammalian
Embryonic Stem Cells
Enzyme Inhibitors
Female
Frontotemporal Lobar Degeneration
Humans
Inclusion Bodies
Male
Methylation
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons
Protein Binding
Protein-Arginine N-Methyltransferases
RNA-Binding Protein FUS
Rats
beta Karyopherins
English 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.
Language
  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/178129
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