Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation
Open accessAbstract
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.
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FUS activates and recruits the XRCC1-LIG3 complex to sites of oxidative DNA damage in a PARP1-dependent manner.
“and FUS activates and recruits the XRCC1‐LIG3 complex to sites of oxidative DNA damage in a PARP1‐dependent manner (Naumann et al, 2018; Wang et al, 2018a).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Naumann et al, 2018
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- Authors
- Naumann, M., Pal, A., Goswami, A., Lojewski, X., Japtok, J., Vehlow, A., Naujock, M., Günther, R., Jin, M., Stanslowsky, N., Reinhardt, P., Sterneckert, J., Frickenhaus, M., Pan-Montojo, F., Storkebaum, E., Poser, I., Freischmidt, A., Weishaupt, J. H., Holzmann, K., Troost, D., Ludolph, A. C., Boeckers, T. M., Liebau, S., Petri, S., Cordes, N., Hyman, A. A., Wegner, F., Grill, S. W., Weis, J., Storch, A., & Hermann, A.
- Affiliations
- Technische Universität Dresden (DE)
- Universitätsklinikum Aachen (DE)
- German Cancer Research Center (DE)
- Boehringer Ingelheim (Germany) (DE)
- Medizinische Hochschule Hannover (DE)
- AbbVie (Germany) (DE)
- Center for Regenerative Therapies Dresden (DE)
- University of Münster (DE)
- Munich Cluster for Systems Neurology (DE)
- Radboud University Nijmegen (NL)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Universität Ulm (DE)
- University Hospital Ulm (DE)
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Tübingen (DE)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Hermann, Andreas
- ORCID
- Naumann, Marcel
- Goswami, Anand
- Vehlow, Anne
- Günther, René
- Jin, Mengmeng
- Sterneckert, Jared
- Pan-Montojo, Francisco
- Storkebaum, Erik
- Poser, Ina
- Freischmidt, Axel
- Weishaupt, Jochen H.
- Holzmann, Karlheinz
- Ludolph, Albert C.
- Boeckers, Tobias M.
- Liebau, Stefan
- Petri, Susanne
- Cordes, Nils
- Hyman, Anthony A.
- Wegner, Florian
- Grill, Stephan W.
- Weis, Joachim
- Storch, Alexander
- Hermann, Andreas
- Venue
- Nature Communications
- Published
- 2018-01-23
- Volume
- 9
- Issue
- 1
- Pages
- 335-335
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5780468
- OpenAlex
- W2785225651
- Cited by
- 275
- References
- 50
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 25 · 2023: 39 · 2022: 35 · 2021: 45 · 2020: 44 · 2019: 30 · 2018: 18
- FWCI
- 23.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, cc-by)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- RWTH Publications (RWTH Aachen)
- Funders
- Muscular Dystrophy Association
- EU Joint Programme – Neurodegenerative Disease Research (ZonMW 733051073, ZonMW 733051075)
- ZonMw (733051073, 733051075)
- Bundesministerium für Bildung und Forschung
- Technische Universität Dresden
- Max-Planck-Gesellschaft
- NOMIS Stiftung
- Roland Ernst Stiftung
- H2020 European Research Council (770244)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, FUS, nuclear localization signal, DNA damage response, poly(ADP-ribose) polymerase, neurodegeneration, protein aggregation, motor neurons, induced pluripotent stem cell-derived motor neurons, ALS pathogenesis
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Cell Differentiation, Cell Nucleus, Cytoplasm, DNA Damage, Female, Humans, Male, Middle Aged, Motor Neurons, Mutation, Signal Transduction, Gene Expression, Nuclear Localization Signals, Active Transport, Cell Nucleus, RNA-Binding Protein FUS, Induced Pluripotent Stem Cells, Protein Aggregation, Pathological
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