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Nat Commun. 2018 Jan 23;9(1):335. doi: 10.1038/s41467-017-02299-1.

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

Author information

1
Department of Neurology, Technische Universität Dresden, 01307, Dresden, Germany.
2
Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstrasse-30, 52074, Aachen, Germany.
3
OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, 01307, Germany.
4
German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), 69192, Heidelberg, Germany.
5
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328, Dresden, Germany.
6
Department of Neurology, Hannover Medical School, 30625, Hannover, Germany.
7
CNS Research Department, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, 55216, Ingelheim am Rhein, Germany.
8
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307, Dresden, Germany.
9
AbbVie Deutschland GmbH & Co. KG, 67061, Ludwigshafen, Germany.
10
Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149, Münster, Germany.
11
Faculty of Medicine, University of Münster, 48149, Münster, Germany.
12
Department of Neurology, Klinikum der Universität München, and Munich Cluster for Systems Neurology, SyNergy, 81377, Munich, Germany.
13
Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
14
Max Planck Institute of Molecular Cell Biology and Genetics, 01307, Dresden, Germany.
15
Department of Neurology, University Ulm, 89081, Ulm, Germany.
16
Genomics-Core Facility, University Hospital Ulm, Centre for Biomedical Research, 89081, Ulm, Germany.
17
Division of Neuropathology, Department of Pathology, Academic Medical Centre, 1105 AZ, Amsterdam, The Netherlands.
18
Institute of Anatomy and Cell Biology, University of Ulm, 89081, Ulm, Germany.
19
Institute of Neuroanatomy & Developmental Biology, Eberhard Karls University of Tübingen, 72074, Tübingen, Germany.
20
Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany.
21
BIOTEC, Technische Universität Dresden, 01307, Dresden, Germany.
22
German Center for Neurodegenerative Diseases (DZNE), Research Site Rostock, 18147, Rostock, Germany.
23
Department of Neurology, University of Rostock, 18147, Rostock, Germany.
24
Department of Neurology, Technische Universität Dresden, 01307, Dresden, Germany. Andreas.Hermann@uniklinikum-dresden.de.
25
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307, Dresden, Germany. Andreas.Hermann@uniklinikum-dresden.de.
26
German Center for Neurodegenerative Diseases (DZNE), Research Site Rostock, 18147, Rostock, Germany. Andreas.Hermann@uniklinikum-dresden.de.

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.

PMID:
29362359
PMCID:
PMC5780468
DOI:
10.1038/s41467-017-02299-1
[Indexed for MEDLINE]
Free PMC Article

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