| First Author | Woo MS | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 5 | PubMed ID | 33661276 |
| Mgi Jnum | J:311826 | Mgi Id | MGI:6724813 |
| Doi | 10.1084/jem.20201290 | Citation | Woo MS, et al. (2021) Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation. J Exp Med 218(5) |
| abstractText | 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. |
