title: Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.
abstract: FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.
authors.affiliation: Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France.
authors.forename: Jelena
authors.initials: J
authors.lastname: Scekic-Zahirovic
authors.affiliation: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Muenster, Germany Faculty of Medicine, University of Muenster, Muenster, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sendscheid
authors.affiliation: Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France.
authors.forename: Hajer
authors.initials: H
authors.lastname: El Oussini
authors.affiliation: Department of Neurosciences, University of California, San Diego La Jolla, CA, USA Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Jambeau
authors.affiliation: Department of Neurosciences, University of California, San Diego La Jolla, CA, USA Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Muenster, Germany Faculty of Medicine, University of Muenster, Muenster, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Mersmann
authors.affiliation: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Muenster, Germany Faculty of Medicine, University of Muenster, Muenster, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dieterlé
authors.affiliation: Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Sinniger
authors.affiliation: Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dirrig-Grosch
authors.affiliation: Department of Neurosciences, University of California, San Diego La Jolla, CA, USA Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Drenner
authors.affiliation: Institut Clinique de la souris, Illkirch-Graffenstaden, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Birling
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Hairi
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rouaux
authors.affiliation: University of Cardiff, Cardiff, UK.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Shelkovnikova
authors.affiliation: Department of Neurology University of Ulm, Ulm, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Witting
authors.affiliation: Department of Neurology University of Ulm, Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Muenster, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Muenster, Germany Faculty of Medicine, University of Muenster, Muenster, Germany erik.storkebaum@mpi-muenster.mpg.de clagier-tourenne@mgh.harvard.edu ldupuis@unistra.fr.
authors.forename: Erik
authors.initials: E
authors.lastname: Storkebaum
authors.affiliation: Department of Neurosciences, University of California, San Diego La Jolla, CA, USA Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA erik.storkebaum@mpi-muenster.mpg.de clagier-tourenne@mgh.harvard.edu ldupuis@unistra.fr.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.affiliation: Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France erik.storkebaum@mpi-muenster.mpg.de clagier-tourenne@mgh.harvard.edu ldupuis@unistra.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism
chemical_list: C000599551:FUS protein, mouse; D034702:RNA-Binding Protein FUS
keywords: FUS; PY‐NLS; amyotrophic lateral sclerosis; frontotemporal dementia; motor neuron degeneration