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

Marcel Naumann, Arun Pal, Anand Goswami, Xenia Lojewski, Julia Japtok, Anne Vehlow, Maximilian Naujock, René Günther, Mengmeng Jin, Nancy Stanslowsky, Peter Reinhardt, Jared Sterneckert, Marie Frickenhaus, Francisco Pan-Montojo, Erik Storkebaum, Ina Poser, Axel Freischmidt, Jochen H. Weishaupt, Karlheinz Holzmann, Dirk Troost, Albert C. Ludolph, Tobias M. Boeckers, Stefan Liebau, Susanne Petri, Nils Cordes, Anthony A. Hyman, Florian Wegner, Stephan W. Grill, Joachim Weis, Alexander Storch and Andreas Hermann ()
Additional contact information
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
Maximilian Naujock: Hannover Medical School
René Günther: Technische Universität Dresden
Mengmeng Jin: Technische Universität Dresden
Nancy Stanslowsky: Hannover Medical School
Peter Reinhardt: Technische Universität Dresden
Jared Sterneckert: Technische Universität Dresden
Marie Frickenhaus: Max Planck Institute for Molecular Biomedicine
Francisco Pan-Montojo: Klinikum der Universität München, and Munich Cluster for Systems Neurology
Erik Storkebaum: Max Planck Institute for Molecular Biomedicine
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
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
Joachim Weis: RWTH Aachen University Hospital
Alexander Storch: Technische Universität Dresden
Andreas Hermann: Technische Universität Dresden

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02299-1

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