Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation

Marcel S. Woo, Friederike Ufer, Nicola Rothammer, Giovanni Di Liberto, Lars Binkle, Undine Haferkamp, Jana K. Sonner, Jan Broder Engler, Sönke Hornig, Simone Bauer, Ingrid Wagner, Kristof Egervari, Jacob Raber, Robert M. Duvoisin, Ole Pless, Doron Merkler, Manuel A. Friese

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere20201290
JournalJournal of Experimental Medicine
Volume218
Issue number5
DOIs
StatePublished - May 3 2021

ASJC Scopus subject areas

  • Medicine(all)

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