The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis

• Published in: The Journal of clinical investigation Vol. 134; no. 16; pp. 1 - 13
• Main Authors: Woo, Marcel S, Bal, Lukas C, Winschel, Ingo, Manca, Elias, Walkenhorst, Mark, Sevgili, Bachar, Sonner, Jana K, Di Liberto, Giovanni, Mayer, Christina, Binkle-Ladisch, Lars, Rothammer, Nicola, Unger, Lisa, Raich, Lukas, Hadjilaou, Alexandros, Noli, Barbara, Manai, Antonio L, Vieira, Vanessa, Meurs, Nina, Wagner, Ingrid, Pless, Ole, Cocco, Cristina, Stephens, Samuel B, Glatzel, Markus, Merkler, Doron, Friese, Manuel A
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15-08-2024
• Subjects: Alzheimer's disease; Amino acids; Animals; Biopsy; Brain; Care and treatment; Cell death; Cellular signal transduction; Central nervous system; Development and progression; Diagnosis; Excitotoxicity; Flow cytometry; Glucose metabolism; Glutamate; Glutamic acid receptors (metabotropic); Glycolysis; Growth factors; Health aspects; Homeostasis; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammatory diseases; Male; Mice; Mice, Knockout; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Nervous system; Neurodegeneration; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurons; Neurons - metabolism; Neurons - pathology; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Proteins; Risk factors; Signal Transduction; Spinal cord; Toxicity; Germany; Multiple sclerosis; Neuroscience; Inflammation; Neurodegeneration
• ISSN: 0021-9738; 1558-8238; 1558-8238
• 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.