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Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation

Author

Listed:
  • Marcel Naumann

    (Technische Universität Dresden)

  • Arun Pal

    (Technische Universität Dresden)

  • Anand Goswami

    (RWTH Aachen University Hospital)

  • Xenia Lojewski

    (Technische Universität Dresden)

  • Julia Japtok

    (Technische Universität Dresden)

  • Anne Vehlow

    (Helmholtz-Zentrum Dresden-Rossendorf
    partner site Dresden, and German Cancer Research Center (DKFZ)
    Institute of Radiooncology—OncoRay)

  • Maximilian Naujock

    (Hannover Medical School
    Boehringer Ingelheim Pharma GmbH & Co. KG)

  • René Günther

    (Technische Universität Dresden)

  • Mengmeng Jin

    (Technische Universität Dresden)

  • Nancy Stanslowsky

    (Hannover Medical School)

  • Peter Reinhardt

    (Technische Universität Dresden
    AbbVie Deutschland GmbH & Co. KG)

  • Jared Sterneckert

    (Technische Universität Dresden)

  • Marie Frickenhaus

    (Max Planck Institute for Molecular Biomedicine
    University of Münster)

  • Francisco Pan-Montojo

    (Klinikum der Universität München, and Munich Cluster for Systems Neurology)

  • Erik Storkebaum

    (Max Planck Institute for Molecular Biomedicine
    University of Münster
    Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University)

  • Ina Poser

    (Max Planck Institute of Molecular Cell Biology and Genetics)

  • Axel Freischmidt

    (University Ulm)

  • Jochen H. Weishaupt

    (University Ulm)

  • Karlheinz Holzmann

    (Centre for Biomedical Research)

  • Dirk Troost

    (Academic Medical Centre)

  • Albert C. Ludolph

    (University Ulm)

  • Tobias M. Boeckers

    (University of Ulm)

  • Stefan Liebau

    (Eberhard Karls University of Tübingen)

  • Susanne Petri

    (Hannover Medical School)

  • Nils Cordes

    (Helmholtz-Zentrum Dresden-Rossendorf
    partner site Dresden, and German Cancer Research Center (DKFZ)
    Institute of Radiooncology—OncoRay
    Technische Universität Dresden)

  • Anthony A. Hyman

    (Max Planck Institute of Molecular Cell Biology and Genetics)

  • Florian Wegner

    (Hannover Medical School)

  • Stephan W. Grill

    (Max Planck Institute of Molecular Cell Biology and Genetics
    Technische Universität Dresden)

  • Joachim Weis

    (RWTH Aachen University Hospital)

  • Alexander Storch

    (Technische Universität Dresden
    Technische Universität Dresden
    German Center for Neurodegenerative Diseases (DZNE), Research Site Rostock
    University of Rostock)

  • Andreas Hermann

    (Technische Universität Dresden
    Technische Universität Dresden
    German Center for Neurodegenerative Diseases (DZNE), Research Site Rostock)

Abstract

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS.

Suggested Citation

  • Marcel Naumann & Arun Pal & Anand Goswami & Xenia Lojewski & Julia Japtok & Anne Vehlow & Maximilian Naujock & René Günther & Mengmeng Jin & Nancy Stanslowsky & Peter Reinhardt & Jared Sterneckert & M, 2018. "Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02299-1
    DOI: 10.1038/s41467-017-02299-1
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