Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Biomedical Sciences, NEF-Laboratory, University of Cagliari, Monserrato, Cagliari, Italy.
J Clin Invest. 2024 Jun 18;134(16):e177692. doi: 10.1172/JCI177692.
A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration.
兴奋与抑制失衡（E/I 平衡）被越来越多地认为是多发性硬化症（MS）——一种中枢神经系统的慢性炎症性疾病——神经退行性变的关键驱动因素。为了了解慢性过度兴奋如何导致 MS 中的神经元丧失，我们对 E/I 平衡失调和易患炎症诱导的神经退行性变的缺乏抑制性代谢型谷氨酸信号的小鼠神经元进行了转录谱分析。这揭示了核受体 NR4A2 在神经元中的显著诱导。从机制上讲，NR4A2 通过刺激连续的 VGF 分泌导致依赖糖酵解的神经元细胞死亡，从而增加了对兴奋性毒性的易感性。将这些发现扩展到多发性硬化症患者（pwMS），我们观察到血清和脑活检中 VGF 水平升高。值得注意的是，在 MS 的小鼠模型中神经元特异性缺失 Vgf 可改善神经退行性变。这些发现强调了由兴奋活动驱动的持续代谢转变作为炎症诱导的神经退行性变的基本机制的有害影响。
