Cellular and Molecular Life Sciences

, Volume 74, Issue 2, pp 339–358 | Cite as

Disruption of calcitonin gene-related peptide signaling accelerates muscle denervation and dampens cytotoxic neuroinflammation in SOD1 mutant mice

  • Cornelia Ringer
  • Sarah Tune
  • Mirjam A Bertoune
  • Hans Schwarzbach
  • Kazutake Tsujikawa
  • Eberhard Weihe
  • Burkhard Schütz
Original Article


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.


Astrocyte Chemokine Microglia Neuropeptide Receptor activity-modifying protein 1 Superoxide dismutase 1 







Amyotrophic lateral sclerosis


Brain-derived neurotrophic factor


Choline acetyltransferase


Cluster of differentiation


Calcitonin gene-related peptide


Calcitonin receptor-like receptor


Glial cell line-derived neurotrophic factor


Glial fibrillary acidic protein


Ionized calcium-binding adapter molecule 1






Neuromuscular junction


Postnatal day


Paw grip endurance test


Receptor activity-modifying protein 1


Receptor component protein


Reverse transcriptase polymerase chain reaction


Superoxide dismutase 1


Transforming growth factor


Tumor necrosis factor


Vesicular acetylcholine transporter


Vascular endothelial growth factor


Ventral horn




Hypoglossal nucleus


Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide



We are grateful to Carola Gäckler, Michael Schneider, and Marion Zibuschka for excellent technical assistance. This work was supported by funds from the University Medical Center Giessen and Marburg (UKGM), by the P. E. Kempkes Foundation (University of Marburg), and by grants from the German Society for the Muscular Diseased (DGM, Freiburg, Germany).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

18_2016_2337_MOESM1_ESM.jpg (1 mb)
Supplementary material 1 (JPEG 1056 kb) Supplemental Figure: Spatio-temporal correlations between vacuolization, astrogliosis, and CGRP abundance in SOD1 mice. (A) Time course of vacuole development in the facial motor nucleus in SOD1 mice detected by CGRP immunoreactivity. CGRP immunoreactivities found in the facial (VII) nuclei (upper panel) and in the surrounding neuropil (lower panel) at pre-symptomatic (P30, a + b; P50, c + d) and symptomatic (P90, e + f; end stage, g + h) stages. Note immunoreactive swellings in neurites at P30 that could be either vesicles or very early stages of pathophysiological vacuoles (arrows in b), while vacuoles with a small (1-2 µm), but visible lumen occur at P50 in the neuropil (arrows in d). Also note that vacuoles increased in size and also appeared in soma of VII motor neurons (insert in e), reaching up to 20 µm in diameter until end stage (arrowhead in g), thus being as big as the few surviving motor neurons (arrows in g). The bar in (a) equals 50 µm and accounts for all pictures of the upper panel. The bar in (b) equals 20 µm and accounts for all pictures of the lower panel. The bar in the insert in e equals 10 µm. (B) Qualitative assessment of vacuolization and astrogliosis in non-somatomotor areas in end-stage SOD1 mice. Double immunofluorescence for SOD1 (red label) and GFAP (green label) in the inferior olive, accumbens nucleus, substantia nigra, and locus coeruleus. Note the varying degrees of both vacuolization, i.e., number and size of SOD1-immunoreactive vacuoles, and astrogliosis, i.e., number and size of GFAP-immunoreactive astrocytes. The bar equals 50 µm and accounts for all pictures. (C) Quantitative assessment of vacuolization and astrogliosis in 18 regions throughout the brain. Quantification of GFAP (top) and SOD1 (bottom) immunoreactivities in WT and early and late-stage SOD1 mice. All data presented as mean ± SEM. P, postnatal day; *, significant change compared with WT; #, significant change compared with early disease stage. For a description of brain area abbreviations: see Table 1


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Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Cornelia Ringer
    • 1
    • 2
  • Sarah Tune
    • 3
  • Mirjam A Bertoune
    • 4
  • Hans Schwarzbach
    • 4
  • Kazutake Tsujikawa
    • 5
  • Eberhard Weihe
    • 1
  • Burkhard Schütz
    • 1
  1. 1.Department of Molecular Neurosciences, Institute of Anatomy and Cell BiologyPhilipps-UniversityMarburgGermany
  2. 2.Institute of AnatomyUniversity of LübeckLübeckGermany
  3. 3.Department of PhysiologyUniversity of LübeckLübeckGermany
  4. 4.Department of Medical Cell Biology, Institute of Anatomy and Cell BiologyPhilipps-UniversityMarburgGermany
  5. 5.Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical SciencesOsaka UniversitySuitaJapan

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