Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Division of Clinical Pathology, Department of Pathology and Immunology, Geneva Faculty of Medicine, Geneva, Switzerland.
J Exp Med. 2021 May 3;218(5). doi: 10.1084/jem.20201290.
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.
多发性硬化症（MS）是一种中枢神经系统的慢性炎症性疾病，伴有持续的神经元丧失。由于缺乏对炎症诱导的神经退行性通路的了解，临床进展的治疗仍然具有挑战性。在这里，我们表明，神经元受体相互作用组的失衡正在驱动 MS 患者神经元中的谷氨酸兴奋性毒性，并确定与 MS 相关的代谢型谷氨酸受体 8（GRM8）作为决定性的调节剂。在机制上，GRM8 的激活抵消了神经元 cAMP 的积累，从而直接使肌醇 1,4,5-三磷酸受体（IP3R）脱敏。这极大地限制了谷氨酸从内质网引发的钙释放和随后的细胞死亡。值得注意的是，我们发现 Grm8 缺陷型神经元更容易发生谷氨酸兴奋性毒性，而 GRM8 的药理学激活增强了小鼠和人类神经元以及 MS 临床前小鼠模型中的神经保护作用。因此，我们证明 GRM8 赋予神经元对中枢神经系统炎症的弹性，并且是一个具有广泛治疗意义的有前途的神经保护靶标。
