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TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis

Abstract

In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the antidiabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4−/− mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.

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Figure 1: Trpm4 deletion reduces disease severity in EAE mice.
Figure 2: Trpm4−/− mice show no EAE-relevant immune system alterations.
Figure 3: Neuronal and axonal expression of TRPM4 in mice and humans.
Figure 4: Trpm4−/− mice show reduced neurodegeneration during EAE.
Figure 5: TRPM4 contributes to excitotoxic cell death in vitro.
Figure 6: Glibenclamide reduces neurodegeneration in EAE.

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References

  1. 1

    Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 1502–1517 (2008).

    CAS  PubMed  Google Scholar 

  2. 2

    Kornek, B. et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 157, 267–276 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Lovas, G., Szilagyi, N., Majtenyi, K., Palkovits, M. & Komoly, S. Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123, 308–317 (2000).

    PubMed  Google Scholar 

  4. 4

    Tallantyre, E.C. et al. Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis. Mult. Scler. 16, 406–411 (2010).

    PubMed  Google Scholar 

  5. 5

    Fisher, E., Lee, J.C., Nakamura, K. & Rudick, R.A. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann. Neurol. 64, 255–265 (2008).

    PubMed  Google Scholar 

  6. 6

    Fisniku, L.K. et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann. Neurol. 64, 247–254 (2008).

    PubMed  Google Scholar 

  7. 7

    Lucchinetti, C.F. et al. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 365, 2188–2197 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Frischer, J.M. et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132, 1175–1189 (2009).

    PubMed  PubMed Central  Google Scholar 

  9. 9

    Trapp, B.D. & Stys, P.K. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 8, 280–291 (2009).

    CAS  PubMed  Google Scholar 

  10. 10

    Nikić, I. et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 17, 495–499 (2011).

    PubMed  PubMed Central  Google Scholar 

  11. 11

    Pitt, D., Werner, P. & Raine, C.S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6, 67–70 (2000).

    CAS  PubMed  Google Scholar 

  12. 12

    Smith, T., Groom, A., Zhu, B. & Turski, L. Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat. Med. 6, 62–66 (2000).

    CAS  PubMed  Google Scholar 

  13. 13

    Basso, A.S. et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J. Clin. Invest. 118, 1532–1543 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Baranzini, S.E. et al. Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis. Brain 133, 2603–2611 (2010).

    PubMed  PubMed Central  Google Scholar 

  15. 15

    Stover, J.F. et al. Neurotransmitters in cerebrospinal fluid reflect pathological activity. Eur. J. Clin. Invest. 27, 1038–1043 (1997).

    CAS  PubMed  Google Scholar 

  16. 16

    Werner, P., Pitt, D. & Raine, C.S. Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann. Neurol. 50, 169–180 (2001).

    CAS  PubMed  Google Scholar 

  17. 17

    Bal-Price, A. & Brown, G.C. Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J. Neurosci. 21, 6480–6491 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Campbell, G.R. et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann. Neurol. 69, 481–492 (2011).

    CAS  PubMed  Google Scholar 

  19. 19

    Dutta, R. et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol. 59, 478–489 (2006).

    CAS  PubMed  Google Scholar 

  20. 20

    Mahad, D.J. et al. Mitochondrial changes within axons in multiple sclerosis. Brain 132, 1161–1174 (2009).

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Craner, M.J. et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc. Natl. Acad. Sci. USA 101, 8168–8173 (2004).

    CAS  PubMed  Google Scholar 

  22. 22

    Friese, M.A. et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat. Med. 13, 1483–1489 (2007).

    CAS  PubMed  Google Scholar 

  23. 23

    Vergo, S. et al. Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Brain 134, 571–584 (2011).

    PubMed  Google Scholar 

  24. 24

    Barbet, G. et al. The calcium-activated nonselective cation channel TRPM4 is essential for the migration but not the maturation of dendritic cells. Nat. Immunol. 9, 1148–1156 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Launay, P. et al. TRPM4 regulates calcium oscillations after T cell activation. Science 306, 1374–1377 (2004).

    CAS  PubMed  Google Scholar 

  26. 26

    Vennekens, R. et al. Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nat. Immunol. 8, 312–320 (2007).

    CAS  PubMed  Google Scholar 

  27. 27

    Guinamard, R., Demion, M. & Launay, P. Physiological roles of the TRPM4 channel extracted from background currents. Physiology (Bethesda) 25, 155–164 (2010).

    CAS  Google Scholar 

  28. 28

    Launay, P. et al. TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell 109, 397–407 (2002).

    CAS  PubMed  Google Scholar 

  29. 29

    Nilius, B. et al. Regulation of the Ca2+ sensitivity of the nonselective cation channel TRPM4. J. Biol. Chem. 280, 6423–6433 (2005).

    CAS  PubMed  Google Scholar 

  30. 30

    Nilius, B., Prenen, J., Voets, T. & Droogmans, G. Intracellular nucleotides and polyamines inhibit the Ca2+-activated cation channel TRPM4b. Pflugers Arch. 448, 70–75 (2004).

    CAS  PubMed  Google Scholar 

  31. 31

    Murakami, M. et al. Identification and characterization of the murine TRPM4 channel. Biochem. Biophys. Res. Commun. 307, 522–528 (2003).

    CAS  PubMed  Google Scholar 

  32. 32

    Nilius, B. et al. Voltage dependence of the Ca2+-activated cation channel TRPM4. J. Biol. Chem. 278, 30813–30820 (2003).

    CAS  PubMed  Google Scholar 

  33. 33

    Xu, X.Z., Moebius, F., Gill, D.L. & Montell, C. Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform. Proc. Natl. Acad. Sci. USA 98, 10692–10697 (2001).

    CAS  PubMed  Google Scholar 

  34. 34

    Mathar, I. et al. Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice. J. Clin. Invest. 120, 3267–3279 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Gerzanich, V. et al. De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nat. Med. 15, 185–191 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Kruse, M. et al. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J. Clin. Invest. 119, 2737–2744 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Yoo, J.C. et al. Cloning and characterization of rat transient receptor potential-melastatin 4 (TRPM4). Biochem. Biophys. Res. Commun. 391, 806–811 (2010).

    CAS  PubMed  Google Scholar 

  38. 38

    Mironov, S.L. Metabotropic glutamate receptors activate dendritic calcium waves and TRPM channels which drive rhythmic respiratory patterns in mice. J. Physiol. (Lond.) 586, 2277–2291 (2008).

    CAS  Google Scholar 

  39. 39

    Armstrong, W.E., Wang, L., Li, C. & Teruyama, R. Performance, properties and plasticity of identified oxytocin and vasopressin neurones in vitro. J. Neuroendocrinol. 22, 330–342 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Shpak, G., Zylbertal, A., Yarom, Y. & Wagner, S. Calcium-activated sustained firing responses distinguish accessory from main olfactory bulb mitral cells. J. Neurosci. 32, 6251–6262 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Weber, K.S., Hildner, K., Murphy, K.M. & Allen, P.M. Trpm4 differentially regulates TH1 and TH2 function by altering calcium signaling and NFAT localization. J. Immunol. 185, 2836–2846 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Anand, N. & Stead, L.G. Neuron-specific enolase as a marker for acute ischemic stroke: a systematic review. Cerebrovasc. Dis. 20, 213–219 (2005).

    CAS  PubMed  Google Scholar 

  43. 43

    Demion, M., Bois, P., Launay, P. & Guinamard, R. TRPM4, a Ca2+-activated nonselective cation channel in mouse sino-atrial node cells. Cardiovasc. Res. 73, 531–538 (2007).

    CAS  PubMed  Google Scholar 

  44. 44

    Becerra, A. et al. Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death. Cardiovasc. Res. 91, 677–684 (2011).

    CAS  PubMed  Google Scholar 

  45. 45

    Chen, M., Dong, Y. & Simard, J.M. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J. Neurosci. 23, 8568–8577 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Feyerabend, T.B. et al. Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell–mediated autoimmunity. Immunity 35, 832–844 (2011).

    CAS  PubMed  Google Scholar 

  47. 47

    Groom, A.J., Smith, T. & Turski, L. Multiple sclerosis and glutamate. Ann. NY Acad. Sci. 993, 229–275 (2003).

    CAS  PubMed  Google Scholar 

  48. 48

    Lau, A. & Tymianski, M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch. 460, 525–542 (2010).

    CAS  PubMed  Google Scholar 

  49. 49

    Nilius, B. et al. The Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5-biphosphate. EMBO J. 25, 467–478 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Zhang, Z., Okawa, H., Wang, Y. & Liman, E.R. Phosphatidylinositol 4,5-bisphosphate rescues TRPM4 channels from desensitization. J. Biol. Chem. 280, 39185–39192 (2005).

    CAS  PubMed  Google Scholar 

  51. 51

    Schinder, A.F., Olson, E.C., Spitzer, N.C. & Montal, M. Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J. Neurosci. 16, 6125–6133 (1996).

    CAS  PubMed  Google Scholar 

  52. 52

    Sun, L. & June Liu, S. Activation of extrasynaptic NMDA receptors induces a PKC-dependent switch in AMPA receptor subtypes in mouse cerebellar stellate cells. J. Physiol. (Lond.) 583, 537–553 (2007).

    CAS  Google Scholar 

  53. 53

    Crnich, R. et al. Vasoconstriction resulting from dynamic membrane trafficking of TRPM4 in vascular smooth muscle cells. Am. J. Physiol. Cell Physiol. 299, C682–C694 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Lan, J.Y. et al. Protein kinase C modulates NMDA receptor trafficking and gating. Nat. Neurosci. 4, 382–390 (2001).

    CAS  PubMed  Google Scholar 

  55. 55

    Fisher, E. et al. Imaging correlates of axonal swelling in chronic multiple sclerosis brains. Ann. Neurol. 62, 219–228 (2007).

    PubMed  Google Scholar 

  56. 56

    Stirling, D.P. & Stys, P.K. Mechanisms of axonal injury: internodal nanocomplexes and calcium deregulation. Trends Mol. Med. 16, 160–170 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Rendell, M. The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs 64, 1339–1358 (2004).

    CAS  PubMed  Google Scholar 

  58. 58

    Lucchinetti, C. et al. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain 122, 2279–2295 (1999).

    PubMed  Google Scholar 

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Acknowledgements

M.A.F. is supported by the Deutsche Forschungsgemeinschaft Emmy Noether-Programme (FR1720/3-1) and the Gemeinnützige Hertie-Stiftung (1.01.1/11/003). D.M. is supported by the Swiss National Science Foundation (PP00P3_128372). O.P. is supported by the Gemeinnützige Hertie-Stiftung. We would like to thank N. Lin Marq and N. Kursawe for excellent technical assistance.

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B.S. organized the study, performed the main experimental work and drafted the manuscript. K.S. performed most immunological experiments and helped with additional experimental procedures, and writing of the manuscript. K.S., W.B. and D.M. did histopathological evaluations of mouse EAE and human CNS tissue, and participated in data discussion. M. Kruse performed electrophysiological recordings. E.T. and M. Kneussel performed several neuronal cell culture experiments. F.U. helped with additional experimental procedures. R.V., V.F. and M.F. provided Trpm4−/− mice, participated in data discussion and edited the manuscript. A.M. and R.V. provided some calcium imaging data. O.P. and M. Kneussel participated in data discussion. D.M. conceived experiments, provided funding for the research and took part in manuscript writing. M.A.F. conceived and designed the study, oversaw and directed the experiments, provided the funding for the research and wrote the manuscript.

Corresponding author

Correspondence to Manuel A Friese.

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Competing interests

The Universitätsklinikum Hamburg-Eppendorf, the Universität des Saarlandes and the Université de Genève have filed a patent application entitled “Novel methods for treating or preventing neurodegeneration” (European patent application No. EP11196121.5), which is based on the research described in this paper. M.A.F., B.S., K.S., D.M., M.F., V.F. and R.V. are listed as inventors in this application.

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Schattling, B., Steinbach, K., Thies, E. et al. TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 18, 1805–1811 (2012). https://doi.org/10.1038/nm.3015

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