Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation

J Exp Med. 2021 May 3;218(5):e20201290. doi: 10.1084/jem.20201290.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / genetics
  • Cells, Cultured
  • Central Nervous System / metabolism*
  • Central Nervous System / pathology
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Gene Expression Profiling / methods
  • Gene Regulatory Networks / genetics
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / metabolism
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Neuroprotective Agents / metabolism
  • Receptors, Metabotropic Glutamate / genetics*
  • Receptors, Metabotropic Glutamate / metabolism
  • Signal Transduction / genetics

Substances

  • Neuroprotective Agents
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 8