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Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation

Woo, Marcel S., Ufer, Friederike, Rothammer, Nicola, Di Liberto, Giovanni, Binkle, Lars, Haferkamp, Undine, Sonner, Jana K., Engler, Jan Broder, Hornig, Sönke, Bauer, Simone, Wagner, Ingrid, Egervari, Kristof, Raber, Jacob, Duvoisin, Robert M., Pless, Ole, Merkler, Doron, Friese, Manuel A.·2021·Journal of Experimental Medicine
DOI 10.1084/jem.20201290PMC PMC7938362
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Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk–associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications.

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Metadata

Authors
Woo, M. S., Ufer, F., Rothammer, N., Di Liberto, G., Binkle, L., Haferkamp, U., Sonner, J. K., Engler, J. B., Hornig, S., Bauer, S., Wagner, I., Egervari, K., Raber, J., Duvoisin, R. M., Pless, O., Merkler, D., & Friese, M. A.
Affiliations
  • Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany 1
  • Division of Clinical Pathology, Department of Pathology and Immunology, Geneva Faculty of Medicine, Geneva, Switzerland 2
  • Fraunhofer Institute for Translational Medicine and Pharmacology, Hamburg, Germany 3
  • Experimentelle Neuropädiatrie, Klinik für Kinder und Jugendmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany 4
  • Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 5
  • Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 9
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2021-03-04
Volume
218
Issue
5
ISSN
  • 0022-1007
  • 1540-9538
DOI
10.1084/jem.20201290
PMC
PMC7938362
Cited by
56
References
15
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Deutsche Forschungsgemeinschaft (FR1720/9-2, SFB1328, A06, A16)
  • Gemeinnützige Hertie-Stiftung (P1170053)
  • Swiss National Science Foundation
  • Else Kröner-Fresenius Foundation

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