title: Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.
abstract: Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease.
authors.affiliation: Inserm, UMR-S1118, 67085, Strasbourg, France.|Faculté de Médecine, UMR-S1118, Université de Strasbourg, 67085, Strasbourg, France.
authors.forename: Jelena
authors.initials: J
authors.lastname: Scekic-Zahirovic
authors.affiliation: Inserm, UMR-S1118, 67085, Strasbourg, France.|Faculté de Médecine, UMR-S1118, Université de Strasbourg, 67085, Strasbourg, France.
authors.forename: Hajer El
authors.initials: HE
authors.lastname: Oussini
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: Department of Neurosciences, Ludwig Institute for Cancer Research, University of California, San Diego, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Drenner
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: Department of Neurosciences, Ludwig Institute for Cancer Research, University of California, San Diego, 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: Kira
authors.initials: K
authors.lastname: Allmeroth
authors.affiliation: Inserm, UMR-S1118, 67085, Strasbourg, France.|Faculté de Médecine, UMR-S1118, Université de Strasbourg, 67085, Strasbourg, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dieterlé
authors.affiliation: Inserm, UMR-S1118, 67085, Strasbourg, France.|Faculté de Médecine, UMR-S1118, Université de Strasbourg, 67085, Strasbourg, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Sinniger
authors.affiliation: Inserm, UMR-S1118, 67085, Strasbourg, France.|Faculté de Médecine, UMR-S1118, Université de Strasbourg, 67085, Strasbourg, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dirrig-Grosch
authors.affiliation: Inserm, UMR-S1118, 67085, Strasbourg, France.|Faculté de Médecine, UMR-S1118, Université de Strasbourg, 67085, Strasbourg, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: René
authors.affiliation: BioMedical Center (BMC), Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Dormann
authors.affiliation: Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|BioMedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Department of Neurosciences, Ludwig Institute for Cancer Research, University of California, San Diego, USA.|Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, 02129, USA.|Broad Institute of Harvard University and MIT, Cambridge, MA, 02142, USA.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.affiliation: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Muenster, Germany. erik.storkebaum@mpi-muenster.mpg.de.|Faculty of Medicine, University of Muenster, Muenster, Germany. erik.storkebaum@mpi-muenster.mpg.de.
authors.forename: Erik
authors.initials: E
authors.lastname: Storkebaum
authors.affiliation: Inserm, UMR-S1118, 67085, Strasbourg, France. ldupuis@unistra.fr.|Faculté de Médecine, UMR-S1118, Université de Strasbourg, 67085, Strasbourg, France. ldupuis@unistra.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: C000599551:FUS protein, mouse; D012333:RNA, Messenger; D034702:RNA-Binding Protein FUS
keywords: Amyotrophic lateral sclerosis; Fronto-temporal dementia; Mouse models; Non-cell autonomous mechanisms; RNA-binding proteins