Advertisement

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

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.

Keywords

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

Abbreviations

αBtx

Alpha-bungarotoxin

ACh

Acetylcholine

ALS

Amyotrophic lateral sclerosis

BDNF

Brain-derived neurotrophic factor

ChAT

Choline acetyltransferase

CD

Cluster of differentiation

CGRP

Calcitonin gene-related peptide

CLR

Calcitonin receptor-like receptor

GDNF

Glial cell line-derived neurotrophic factor

GFAP

Glial fibrillary acidic protein

Iba1

Ionized calcium-binding adapter molecule 1

IL

Interleukin

ir

Immunoreactivity

NMJ

Neuromuscular junction

P

Postnatal day

PaGE

Paw grip endurance test

RAMP1

Receptor activity-modifying protein 1

RCP

Receptor component protein

RT-PCR

Reverse transcriptase polymerase chain reaction

SOD1

Superoxide dismutase 1

TGF

Transforming growth factor

TNF

Tumor necrosis factor

VAChT

Vesicular acetylcholine transporter

VEGF

Vascular endothelial growth factor

VH

Ventral horn

WT

Wildtype

XII

Hypoglossal nucleus

Ywhaz

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

Notes

Acknowledgments

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

References

  1. 1.
    Sendtner M (2014) Motoneuron disease. Handb Exp Pharmacol 220:411–441. doi: 10.1007/978-3-642-45106-5_15 PubMedCrossRefGoogle Scholar
  2. 2.
    Kiernan MC, Vucic S, Cheah BC et al (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955. doi: 10.1016/S0140-6736(10)61156-7 PubMedCrossRefGoogle Scholar
  3. 3.
    Sreedharan J, Brown RHJ (2013) Amyotrophic lateral sclerosis: Problems and prospects. Ann Neurol 74:309–316. doi: 10.1002/ana.24012 PubMedCrossRefGoogle Scholar
  4. 4.
    Van Langenhove T, van der Zee J, Van Broeckhoven C (2012) The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med 44:817–828. doi: 10.3109/07853890.2012.665471 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Kato S (2008) Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences. Acta Neuropathol 115:97–114. doi: 10.1007/s00401-007-0308-4 PubMedCrossRefGoogle Scholar
  6. 6.
    Philips T, Rothstein JD (2015) Rodent models of amyotrophic lateral sclerosis. Curr Protoc Pharmacol 69:5.67.1–5.67.21. doi: 10.1002/0471141755.ph0567s69 CrossRefGoogle Scholar
  7. 7.
    Gurney ME (1994) Transgenic-mouse model of amyotrophic lateral sclerosis. N Engl J Med 331:1721–1722. doi: 10.1056/NEJM199412223312516 PubMedCrossRefGoogle Scholar
  8. 8.
    Kong J, Xu Z (1998) Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci 18:3241–3250PubMedGoogle Scholar
  9. 9.
    Jaarsma D, Haasdijk ED, Grashorn JA et al (2000) Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Neurobiol Dis 7:623–643. doi: 10.1006/nbdi.2000.0299 PubMedCrossRefGoogle Scholar
  10. 10.
    Fischer LR, Culver DG, Tennant P et al (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240PubMedCrossRefGoogle Scholar
  11. 11.
    Pun S, Santos AF, Saxena S et al (2006) Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9:408–419. doi: 10.1038/nn1653 PubMedCrossRefGoogle Scholar
  12. 12.
    Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23:249–256. doi:10.1002/(SICI)1098-1136(199807)23:3<249:AID-GLIA7>3.0.CO;2-#PubMedCrossRefGoogle Scholar
  13. 13.
    Barbeito LH, Pehar M, Cassina P et al (2004) A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res Rev 47:263–274. doi: 10.1016/j.brainresrev.2004.05.003 PubMedCrossRefGoogle Scholar
  14. 14.
    Graves MC, Fiala M, Dinglasan LAV et al (2004) Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Other Motor Neuron Disord 5:213–219PubMedCrossRefGoogle Scholar
  15. 15.
    Beers DR, Henkel JS, Zhao W et al (2008) CD4 + T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci USA 105:15558–15563. doi: 10.1073/pnas.0807419105 PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Schutz B, Reimann J, Dumitrescu-Ozimek L et al (2005) The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J Neurosci 25:7805–7812. doi: 10.1523/JNEUROSCI.2038-05.2005 PubMedCrossRefGoogle Scholar
  17. 17.
    Wimalawansa SJ (1996) Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev 17:533–585PubMedCrossRefGoogle Scholar
  18. 18.
    van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21:649–678PubMedCrossRefGoogle Scholar
  19. 19.
    Evans BN, Rosenblatt MI, Mnayer LO et al (2000) CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem 275:31438–31443. doi: 10.1074/jbc.M005604200 PubMedCrossRefGoogle Scholar
  20. 20.
    Walker CS, Conner AC, Poyner DR, Hay DL (2010) Regulation of signal transduction by calcitonin gene-related peptide receptors. Trends Pharmacol Sci 31:476–483. doi: 10.1016/j.tips.2010.06.006 PubMedCrossRefGoogle Scholar
  21. 21.
    McLatchie LM, Fraser NJ, Main MJ et al (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339. doi: 10.1038/30666 PubMedCrossRefGoogle Scholar
  22. 22.
    Moreno MJ, Terron JA, Stanimirovic DB et al (2002) Characterization of calcitonin gene-related peptide (CGRP) receptors and their receptor-activity-modifying proteins (RAMPs) in human brain microvascular and astroglial cells in culture. Neuropharmacology 42:270–280PubMedCrossRefGoogle Scholar
  23. 23.
    Wang Z, Ma W, Chabot J-G, Quirion R (2010) Morphological evidence for the involvement of microglial p38 activation in CGRP-associated development of morphine antinociceptive tolerance. Peptides 31:2179–2184. doi: 10.1016/j.peptides.2010.08.020 PubMedCrossRefGoogle Scholar
  24. 24.
    Fukuoka T, Tokunaga A, Kondo E et al (1999) Differential regulation of alpha- and beta-CGRP mRNAs within oculomotor, trochlear, abducens, and trigeminal motoneurons in response to axotomy. Brain Res Mol Brain Res 63:304–315PubMedCrossRefGoogle Scholar
  25. 25.
    Nohr D, Schafer MK, Persson S et al (1999) Calcitonin gene-related peptide gene expression in collagen-induced arthritis is differentially regulated in primary afferents and motoneurons: influence of glucocorticoids. Neuroscience 93:759–773PubMedCrossRefGoogle Scholar
  26. 26.
    Weihe E, Nohr D, Schafer MK et al (1995) Calcitonin gene related peptide gene expression in collagen-induced arthritis. Can J Physiol Pharmacol 73:1015–1019PubMedCrossRefGoogle Scholar
  27. 27.
    Rohrenbeck AM, Bette M, Hooper DC et al (1999) Upregulation of COX-2 and CGRP expression in resident cells of the Borna disease virus-infected brain is dependent upon inflammation. Neurobiol Dis 6:15–34. doi: 10.1006/nbdi.1998.0225 PubMedCrossRefGoogle Scholar
  28. 28.
    Weihe E, Bette M, Preuss MA et al (2008) Role of virus-induced neuropeptides in the brain in the pathogenesis of rabies. Dev Biol (Basel) 131:73–81Google Scholar
  29. 29.
    Morara S, Wang L-P, Filippov V et al (2008) Calcitonin gene-related peptide (CGRP) triggers Ca2+ responses in cultured astrocytes and in Bergmann glial cells from cerebellar slices. Eur J Neurosci 28:2213–2220. doi: 10.1111/j.1460-9568.2008.06514.x PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Priller J, Haas CA, Reddington M, Kreutzberg GW (1995) Calcitonin gene-related peptide and ATP induce immediate early gene expression in cultured rat microglial cells. Glia 15:447–457. doi: 10.1002/glia.440150408 PubMedCrossRefGoogle Scholar
  31. 31.
    Haas CA, Reddington M, Kreutzberg GW (1991) Calcitonin gene-related peptide stimulates the induction of c-fos gene expression in rat astrocyte cultures. Eur J Neurosci 3:708–712PubMedCrossRefGoogle Scholar
  32. 32.
    Reddington M, Priller J, Treichel J et al (1995) Astrocytes and microglia as potential targets for calcitonin gene related peptide in the central nervous system. Can J Physiol Pharmacol 73:1047–1049PubMedCrossRefGoogle Scholar
  33. 33.
    Ringer C, Weihe E, Schutz B (2009) Pre-symptomatic alterations in subcellular betaCGRP distribution in motor neurons precede astrogliosis in ALS mice. Neurobiol Dis 35:286–295. doi: 10.1016/j.nbd.2009.05.011 PubMedCrossRefGoogle Scholar
  34. 34.
    Ringer C, Weihe E, Schutz B (2012) Calcitonin gene-related peptide expression levels predict motor neuron vulnerability in the superoxide dismutase 1-G93A mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 45:547–554. doi: 10.1016/j.nbd.2011.09.011 PubMedCrossRefGoogle Scholar
  35. 35.
    Gurney ME, Pu H, Chiu AY et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775PubMedCrossRefGoogle Scholar
  36. 36.
    Tsujikawa K, Yayama K, Hayashi T et al (2007) Hypertension and dysregulated proinflammatory cytokine production in receptor activity-modifying protein 1-deficient mice. Proc Natl Acad Sci USA 104:16702–16707. doi: 10.1073/pnas.0705974104 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Weydt P, Hong SY, Kliot M, Moller T (2003) Assessing disease onset and progression in the SOD1 mouse model of ALS. Neuroreport 14:1051–1054. doi: 10.1097/01.wnr.0000073685.00308.89 PubMedCrossRefGoogle Scholar
  38. 38.
    Hayar A, Bryant JL, Boughter JD, Heck DH (2006) A low-cost solution to measure mouse licking in an electrophysiological setup with a standard analog-to-digital converter. J Neurosci Methods 153:203–207. doi: 10.1016/j.jneumeth.2005.10.023 PubMedCrossRefGoogle Scholar
  39. 39.
    Fuchs A, Ringer C, Bilkei-Gorzo A et al (2010) Downregulation of the potassium chloride cotransporter KCC2 in vulnerable motoneurons in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 69:1057–1070. doi: 10.1097/NEN.0b013e3181f4dcef PubMedCrossRefGoogle Scholar
  40. 40.
    Schutz B, Chen L, Schafer MK et al (2000) Somatomotor neuron-specific expression of the human cholinergic gene locus in transgenic mice. Neuroscience 96:707–722PubMedCrossRefGoogle Scholar
  41. 41.
    Ringer C, Buning LS, Schafer MK et al (2013) PACAP signaling exerts opposing effects on neuroprotection and neuroinflammation during disease progression in the SOD1 (G93A) mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 54C:32–42. doi: 10.1016/j.nbd.2013.02.010 CrossRefGoogle Scholar
  42. 42.
    Jaarsma D, Rognoni F, van Duijn W et al (2001) CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol 102:293–305PubMedGoogle Scholar
  43. 43.
    Leichsenring A, Linnartz B, Zhu XR et al (2006) Ascending neuropathology in the CNS of a mutant SOD1 mouse model of amyotrophic lateral sclerosis. Brain Res 1096:180–195. doi: 10.1016/j.brainres.2006.04.029 PubMedCrossRefGoogle Scholar
  44. 44.
    Taub DD, Oppenheim JJ (1994) Chemokines, inflammation and the immune system. Ther Immunol 1:229–246PubMedGoogle Scholar
  45. 45.
    Ward SG, Westwick J (1998) Chemokines: understanding their role in T-lymphocyte biology. Biochem J 333(Pt 3):457–470PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Ward SG, Bacon K, Westwick J (1998) Chemokines and T lymphocytes: more than an attraction. Immunity 9:1–11PubMedCrossRefGoogle Scholar
  47. 47.
    Arvidsson U, Piehl F, Johnson H et al (1993) The peptidergic motoneurone. Neuroreport 4:849–856PubMedCrossRefGoogle Scholar
  48. 48.
    Behzadi G, Ganji F (2005) Morphological alteration in oro-facial CGRP containing motoneurons due to congenital thyroid hypofunction. Peptides 26:1486–1491. doi: 10.1016/j.peptides.2005.03.053 PubMedCrossRefGoogle Scholar
  49. 49.
    Mora M, Marchi M, Polak JM et al (1989) Calcitonin gene-related peptide immunoreactivity at the human neuromuscular junction. Brain Res 492:404–407PubMedCrossRefGoogle Scholar
  50. 50.
    Choi RC, Yung LY, Dong TT et al (1998) The calcitonin gene-related peptide-induced acetylcholinesterase synthesis in cultured chick myotubes is mediated by cyclic AMP. J Neurochem 71:152–160PubMedCrossRefGoogle Scholar
  51. 51.
    Uchida S, Yamamoto H, Iio S et al (1990) Release of calcitonin gene-related peptide-like immunoreactive substance from neuromuscular junction by nerve excitation and its action on striated muscle. J Neurochem 54:1000–1003PubMedCrossRefGoogle Scholar
  52. 52.
    Sakaguchi M, Inaishi Y, Kashihara Y, Kuno M (1991) Release of calcitonin gene-related peptide from nerve terminals in rat skeletal muscle. J Physiol 434:257–270PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Sala C, Andreose JS, Fumagalli G, Lømo T (1995) Calcitonin gene-related peptide: possible role in formation and maintenance of neuromuscular junctions. J Neurosci 15:520–528PubMedGoogle Scholar
  54. 54.
    New HV, Mudge AW (1986) Calcitonin gene-related peptide regulates muscle acetylcholine receptor synthesis. Nature 323:809–811. doi: 10.1038/323809a0 PubMedCrossRefGoogle Scholar
  55. 55.
    Fontaine B, Klarsfeld A, Changeux JP (1987) Calcitonin gene-related peptide and muscle activity regulate acetylcholine receptor alpha-subunit mRNA levels by distinct intracellular pathways. J Cell Biol 105:1337–1342PubMedCrossRefGoogle Scholar
  56. 56.
    da Costa VL, Lapa AJ, Godinho RO (2001) Short- and long-term influences of calcitonin gene-related peptide on the synthesis of acetylcholinesterase in mammalian myotubes. Br J Pharmacol 133:229–236. doi: 10.1038/sj.bjp.0704069 PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Buffelli M, Pasino E, Cangiano A (2001) In vivo acetylcholine receptor expression induced by calcitonin gene-related peptide in rat soleus muscle. Neuroscience 104:561–567PubMedCrossRefGoogle Scholar
  58. 58.
    Choi RC, Ting AK, Lau FT et al (2007) Calcitonin gene-related peptide induces the expression of acetylcholinesterase-associated collagen ColQ in muscle: a distinction in driving two different promoters between fast- and slow-twitch muscle fibers. J Neurochem 102:1316–1328. doi: 10.1111/j.1471-4159.2007.4630.x PubMedCrossRefGoogle Scholar
  59. 59.
    Fontaine B, Klarsfeld A, Hokfelt T, Changeux JP (1986) Calcitonin gene-related peptide, a peptide present in spinal cord motoneurons, increases the number of acetylcholine receptors in primary cultures of chick embryo myotubes. Neurosci Lett 71:59–65PubMedCrossRefGoogle Scholar
  60. 60.
    Daniels MP (1997) Intercellular communication that mediates formation of the neuromuscular junction. Mol Neurobiol 14:143–170. doi: 10.1007/BF02740654 PubMedCrossRefGoogle Scholar
  61. 61.
    Lu JT, Son YJ, Lee J et al (1999) Mice lacking alpha-calcitonin gene-related peptide exhibit normal cardiovascular regulation and neuromuscular development. Mol Cell Neurosci 14:99–120. doi: 10.1006/mcne.1999.0767 PubMedCrossRefGoogle Scholar
  62. 62.
    Henderson CE, Phillips HS, Pollock RA et al (1994) GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science 266:1062–1064PubMedCrossRefGoogle Scholar
  63. 63.
    Zurn AD, Baetge EE, Hammang JP et al (1994) Glial cell line-derived neurotrophic factor (GDNF), a new neurotrophic factor for motoneurones. Neuroreport 6:113–118PubMedCrossRefGoogle Scholar
  64. 64.
    Oppenheim RW, Houenou LJ, Johnson JE et al (1995) Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Nature 373:344–346. doi: 10.1038/373344a0 PubMedCrossRefGoogle Scholar
  65. 65.
    Yan Q, Matheson C, Lopez OT (1995) In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons. Nature 373:341–344. doi: 10.1038/373341a0 PubMedCrossRefGoogle Scholar
  66. 66.
    Hottinger AF, Azzouz M, Déglon N et al (2000) Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus. J Neurosci 20:5587–5593PubMedGoogle Scholar
  67. 67.
    Rosa E, Cha J, Bain JR, Fahnestock M (2015) Calcitonin gene-related peptide regulation of glial cell-line derived neurotrophic factor in differentiated rat myotubes. J Neurosci Res 93:514–520. doi: 10.1002/jnr.23512 PubMedCrossRefGoogle Scholar
  68. 68.
    Ramer MS, Bradbury EJ, Michael GJ et al (2003) Glial cell line-derived neurotrophic factor increases calcitonin gene-related peptide immunoreactivity in sensory and motoneurons in vivo. Eur J Neurosci 18:2713–2721PubMedCrossRefGoogle Scholar
  69. 69.
    Blesch A, Tuszynski MH (2001) GDNF gene delivery to injured adult CNS motor neurons promotes axonal growth, expression of the trophic neuropeptide CGRP, and cellular protection. J Comp Neurol 436:399–410PubMedCrossRefGoogle Scholar
  70. 70.
    Glass CK, Saijo K, Winner B et al (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934. doi: 10.1016/j.cell.2010.02.016 PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Appel SH, Beers DR, Henkel JS (2010) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31:7–17. doi: 10.1016/j.it.2009.09.003 PubMedCrossRefGoogle Scholar
  72. 72.
    Umeda Y, Arisawa M (1989) Characterization of the calcitonin gene-related peptide receptor in mouse T lymphocytes. Neuropeptides 14:237–242PubMedCrossRefGoogle Scholar
  73. 73.
    Morara S, Wimalawansa SJ, Rosina A (1998) Monoclonal antibodies reveal expression of the CGRP receptor in Purkinje cells, interneurons and astrocytes of rat cerebellar cortex. Neuroreport 9:3755–3759PubMedCrossRefGoogle Scholar
  74. 74.
    De Corato A, Lisi L, Capuano A et al (2011) Trigeminal satellite cells express functional calcitonin gene-related peptide receptors, whose activation enhances interleukin-1β pro-inflammatory effects. J Neuroimmunol 237:39–46. doi: 10.1016/j.jneuroim.2011.05.013 PubMedCrossRefGoogle Scholar
  75. 75.
    Consonni A, Morara S, Codazzi F et al (2011) Inhibition of lipopolysaccharide-induced microglia activation by calcitonin gene related peptide and adrenomedullin. Mol Cell Neurosci. doi: 10.1016/j.mcn.2011.07.006 PubMedPubMedCentralGoogle Scholar
  76. 76.
    Cady RJ, Glenn JR, Smith KM, Durham PL (2011) Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol Pain 7:94. doi: 10.1186/1744-8069-7-94 PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Streit WJ, Xue QS (2009) Life and death of microglia. J Neuroimmune Pharmacol: Off J Soc Neuroimmune Pharmacol 4:371–379. doi: 10.1007/s11481-009-9163-5 CrossRefGoogle Scholar
  78. 78.
    Liao B, Zhao W, Beers DR et al (2012) Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol 237:147–152. doi: 10.1016/j.expneurol.2012.06.011 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol 10:253–263. doi: 10.1016/S1474-4422(11)70015-1 PubMedCrossRefGoogle Scholar
  80. 80.
    Henkel JS, Beers DR, Zhao W, Appel SH (2009) Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol: Off J Soc NeuroImmune Pharmacol 4:389–398. doi: 10.1007/s11481-009-9171-5 CrossRefGoogle Scholar
  81. 81.
    Alexianu ME, Kozovska M, Appel SH (2001) Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57:1282–1289PubMedCrossRefGoogle Scholar
  82. 82.
    Boillee S, Vandevelde C, Cleveland D (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59. doi: 10.1016/j.neuron.2006.09.018 PubMedCrossRefGoogle Scholar
  83. 83.
    Zhao W, Beers DR, Appel SH (2013) Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. J Neuroimmune Pharmacol: Off J Soc Neuroimmune Pharmacol 8:888–899. doi: 10.1007/s11481-013-9489-x CrossRefGoogle Scholar
  84. 84.
    Jeyachandran A, Mertens B, McKissick EA, Mitchell CS (2015) Type I vs. type II cytokine levels as a function of SOD1 G93A mouse amyotrophic lateral sclerosis disease progression. Front Cell Neurosci 9:462. doi: 10.3389/fncel.2015.00462 PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Mir M, Asensio VJ, Tolosa L et al (2009) Tumor necrosis factor alpha and interferon gamma cooperatively induce oxidative stress and motoneuron death in rat spinal cord embryonic explants. Neuroscience 162:959–971. doi: 10.1016/j.neuroscience.2009.05.049 PubMedCrossRefGoogle Scholar
  86. 86.
    Yin HZ, Hsu CI, Yu S et al (2012) TNF-alpha triggers rapid membrane insertion of Ca(2+) permeable AMPA receptors into adult motor neurons and enhances their susceptibility to slow excitotoxic injury. Exp Neurol 238:93–102. doi: 10.1016/j.expneurol.2012.08.004 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Tolosa L, Caraballo-Miralles V, Olmos G, Lladó J (2011) TNF-α potentiates glutamate-induced spinal cord motoneuron death via NF-κB. Mol Cell Neurosci 46:176–186. doi: 10.1016/j.mcn.2010.09.001 PubMedCrossRefGoogle Scholar
  88. 88.
    Tortarolo M, Vallarola A, Lidonnici D et al (2015) Lack of TNF-alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression. J Neurochem. doi: 10.1111/jnc.13154 PubMedGoogle Scholar
  89. 89.
    Katsuno M, Adachi H, Banno H et al (2011) Transforming growth factor-β signaling in motor neuron diseases. Curr Mol Med 11:48–56PubMedCrossRefGoogle Scholar
  90. 90.
    Spooren A, Kolmus K, Laureys G et al (2011) Interleukin-6, a mental cytokine. Brain Res Rev 67:157–183. doi: 10.1016/j.brainresrev.2011.01.002 PubMedCrossRefGoogle Scholar
  91. 91.
    Evans MC, Couch Y, Sibson N, Turner MR (2013) Inflammation and neurovascular changes in amyotrophic lateral sclerosis. Mol Cell Neurosci 53:34–41. doi: 10.1016/j.mcn.2012.10.008 PubMedCrossRefGoogle Scholar
  92. 92.
    Endo F, Komine O, Fujimori-Tonou N et al (2015) Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells. Cell Rep 11:592–604. doi: 10.1016/j.celrep.2015.03.053 PubMedCrossRefGoogle Scholar
  93. 93.
    Krady JK, Lin H-W, Liberto CM et al (2008) Ciliary neurotrophic factor and interleukin-6 differentially activate microglia. J Neurosci Res 86:1538–1547. doi: 10.1002/jnr.21620 PubMedCrossRefGoogle Scholar
  94. 94.
    Eskes C, Honegger P, Juillerat-Jeanneret L, Monnet-Tschudi F (2002) Microglial reaction induced by noncytotoxic methylmercury treatment leads to neuroprotection via interactions with astrocytes and IL-6 release. Glia 37:43–52. doi: 10.1002/glia.10019 PubMedCrossRefGoogle Scholar
  95. 95.
    Murphy PG, Borthwick LA, Altares M et al (2000) Reciprocal actions of interleukin-6 and brain-derived neurotrophic factor on rat and mouse primary sensory neurons. Eur J Neurosci 12:1891–1899PubMedCrossRefGoogle Scholar
  96. 96.
    Beers DR, Henkel JS, Zhao W et al (2011) Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134:1293–1314. doi: 10.1093/brain/awr074 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    McGillis JP, Humphreys S, Reid S (1991) Characterization of functional calcitonin gene-related peptide receptors on rat lymphocytes. J Immunol 147:3482–3489PubMedGoogle Scholar
  98. 98.
    Foster CA, Mandak B, Kromer E, Rot A (1992) Calcitonin gene-related peptide is chemotactic for human T lymphocytes. Ann N Y Acad Sci 657:397–404PubMedCrossRefGoogle Scholar
  99. 99.
    Talme T, Liu Z, Sundqvist K (2008) The neuropeptide calcitonin gene-related peptide (CGRP) stimulates T cell migration into collagen matrices. J Neuroimmunol 196:60–66. doi: 10.1016/j.jneuroim.2008.02.007 PubMedCrossRefGoogle Scholar
  100. 100.
    Levite M (2000) Nerve-driven immunity. The direct effects of neurotransmitters on T-cell function. Ann N Y Acad Sci 917:307–321PubMedCrossRefGoogle Scholar
  101. 101.
    Mikami N, Watanabe K, Hashimoto N et al (2012) Calcitonin gene-related peptide enhances experimental autoimmune encephalomyelitis by promoting Th17-cell functions. Int Immunol 24:681–691. doi: 10.1093/intimm/dxs075 PubMedCrossRefGoogle Scholar
  102. 102.
    Oh JW, Van Wagoner NJ, Rose-John S, Benveniste EN (1998) Role of IL-6 and the soluble IL-6 receptor in inhibition of VCAM-1 gene expression. J Immunol 161:4992–4999PubMedGoogle Scholar
  103. 103.
    Rosenman SJ, Shrikant P, Dubb L et al (1995) Cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) by astrocytes and astrocytoma cell lines. J Immunol 154:1888–1899PubMedGoogle Scholar
  104. 104.
    Shrikant P, Weber E, Jilling T, Benveniste EN (1995) Intercellular adhesion molecule-1 gene expression by glial cells. Differential mechanisms of inhibition by IL-10 and IL-6. J Immunol 155:1489–1501PubMedGoogle Scholar
  105. 105.
    Desai AJ, Roberts DJ, Richards GO, Skerry TM (2014) Role of receptor activity modifying protein 1 in function of the calcium sensing receptor in the human TT thyroid carcinoma cell line. PLoS One 9:e85237. doi: 10.1371/journal.pone.0085237 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Bouschet T, Martin S, Henley JM (2005) Receptor-activity-modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane. J Cell Sci 118:4709–4720. doi: 10.1242/jcs.02598 PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Christopoulos A, Christopoulos G, Morfis M et al (2003) Novel receptor partners and function of receptor activity-modifying proteins. J Biol Chem 278:3293–3297. doi: 10.1074/jbc.C200629200 PubMedCrossRefGoogle Scholar
  108. 108.
    Ho C, Conner DA, Pollak MR et al (1995) A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 11:389–394. doi: 10.1038/ng1295-389 PubMedCrossRefGoogle Scholar
  109. 109.
    Hay DL, Pioszak AA (2016) Receptor activity-modifying proteins (RAMPs): new insights and roles. Annu Rev Pharmacol Toxicol 56:469–487. doi: 10.1146/annurev-pharmtox-010715-103120 PubMedCrossRefGoogle Scholar

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

Personalised recommendations