title: Tweak regulates astrogliosis, microgliosis and skeletal muscle atrophy in a mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that primarily affects motoneurons in the brain and spinal cord. Astrocyte and microglia activation as well as skeletal muscle atrophy are also typical hallmarks of the disease. However, the functional relationship between astrocytes, microglia and skeletal muscle in the pathogenic process remains unclear. Here, we report that the tumor necrosis factor-like weak inducer of apoptosis (Tweak) and its receptor Fn14 are aberrantly expressed in spinal astrocytes and skeletal muscle of SOD1(G93A) mice. We show that Tweak induces motoneuron death, stimulates astrocytic interleukin-6 release and astrocytic proliferation in vitro. The genetic ablation of Tweak in SOD1(G93A) mice significantly reduces astrocytosis, microgliosis and ameliorates skeletal muscle atrophy. The peripheral neutralization of Tweak through antagonistic anti-Tweak antibody ameliorates muscle pathology and notably, decreases microglial activation in SOD1(G93A) mice. Unexpectedly, none of these approaches improved motor function, lifespan and motoneuron survival. Our work emphasizes the multi-systemic aspect of ALS, and suggests that a combinatorial therapy targeting multiple cell types will be instrumental to halt the neurodegenerative process.
authors.affiliation: The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France, Montpellier University, Montpellier, France.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bowerman
authors.affiliation: The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Salsac
authors.affiliation: The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France, Montpellier University, Montpellier, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Coque
authors.affiliation: The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France.
authors.forename: Émilie
authors.initials: É
authors.lastname: Eiselt
authors.affiliation: The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France.
authors.forename: Roman G
authors.initials: RG
authors.lastname: Deschaumes
authors.affiliation: Inserm UMR1067, Parc Scientifique et Technologique de Luminy, Marseille, France and.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Brodovitch
authors.affiliation: Biogen Idec, Cambridge, MA, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Scamps
authors.affiliation: The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint-Eloi Hospital, 80 rue Augustin Fliche, 34091 Montpellier, France, cedric.raoul@inserm.fr.
authors.forename: Cédric
authors.initials: C
authors.lastname: Raoul
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D049109:Cell Proliferation; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005911:Gliosis / Q000235:genetics*; D015850:Interleukin-6 / Q000096:biosynthesis; D008017:Life Expectancy; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009045:Motor Endplate / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000235:genetics*; D009154:Mutation; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D000074049:Cytokine TWEAK; D015850:Interleukin-6; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1