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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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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.

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Correspondence to Manuel A Friese.

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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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