title: Disruption of calcitonin gene-related peptide signaling accelerates muscle denervation and dampens cytotoxic neuroinflammation in SOD1 mutant mice.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Neuronal vacuolization and glial activation are pathologic hallmarks in the superoxide dismutase 1 (SOD1) mouse model of ALS. Previously, we found the neuropeptide calcitonin gene-related peptide (CGRP) associated with vacuolization and astrogliosis in the spinal cord of these mice. We now show that CGRP abundance positively correlated with the severity of astrogliosis, but not vacuolization, in several motor and non-motor areas throughout the brain. SOD1 mice harboring a genetic depletion of the βCGRP isoform showed reduced CGRP immunoreactivity associated with vacuolization, while motor functions, body weight, survival, and astrogliosis were not altered. When CGRP signaling was completely disrupted through genetic depletion of the CGRP receptor component, receptor activity-modifying protein 1 (RAMP1), hind limb muscle denervation, and loss of muscle performance were accelerated, while body weight and survival were not affected. Dampened neuroinflammation, i.e., reduced levels of astrogliosis in the brain stem already in the pre-symptomatic disease stage, and reduced microgliosis and lymphocyte infiltrations during the late disease phase were additional neuropathology features in these mice. On the molecular level, mRNA expression levels of brain-derived neurotrophic factor (BDNF) and those of the anti-inflammatory cytokine interleukin 6 (IL-6) were elevated, while those of several pro-inflammatory cytokines found reduced in the brain stem of RAMP1-deficient SOD1 mice at disease end stage. Our results thus identify an important, possibly dual role of CGRP in ALS pathogenesis.
authors.affiliation: Department of Molecular Neurosciences, Institute of Anatomy and Cell Biology, Philipps-University, Robert-Koch-Strasse 8, 35037, Marburg, Germany.|Institute of Anatomy, University of Lübeck, Lübeck, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Ringer
authors.affiliation: Department of Physiology, University of Lübeck, Lübeck, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Tune
authors.affiliation: Department of Medical Cell Biology, Institute of Anatomy and Cell Biology, Philipps-University, Marburg, Germany.
authors.forename: Mirjam A
authors.initials: MA
authors.lastname: Bertoune
authors.affiliation: Department of Medical Cell Biology, Institute of Anatomy and Cell Biology, Philipps-University, Marburg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Schwarzbach
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Kazutake
authors.initials: K
authors.lastname: Tsujikawa
authors.affiliation: Department of Molecular Neurosciences, Institute of Anatomy and Cell Biology, Philipps-University, Robert-Koch-Strasse 8, 35037, Marburg, Germany. weihe@staff.uni-marburg.de.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Weihe
authors.affiliation: Department of Molecular Neurosciences, Institute of Anatomy and Cell Biology, Philipps-University, Robert-Koch-Strasse 8, 35037, Marburg, Germany. schuetzb@staff.uni-marburg.de.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Schütz
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D016923:Cell Death; D018925:Chemokines / Q000378:metabolism; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D006824:Hybridization, Genetic; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D008214:Lymphocytes / Q000473:pathology; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009121:Muscle Denervation; D009414:Nerve Growth Factors / Q000378:metabolism; D058262:Receptor Activity-Modifying Protein 1 / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction; D000072105:Superoxide Dismutase-1 / Q000235:genetics* / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism
chemical_list: D018925:Chemokines; D009414:Nerve Growth Factors; C545505:Ramp1 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; D000072105:Superoxide Dismutase-1; D015740:Calcitonin Gene-Related Peptide
keywords: Astrocyte; Chemokine; Microglia; Neuropeptide; Receptor activity-modifying protein 1; Superoxide dismutase 1