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The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis
Marcel S. Woo, … , Doron Merkler, Manuel A. Friese
Marcel S. Woo, … , Doron Merkler, Manuel A. Friese
Published August 15, 2024
Citation Information: J Clin Invest. 2024;134(16):e177692. https://doi.org/10.1172/JCI177692.
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Research Article Inflammation Neuroscience Article has an altmetric score of 8

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

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Abstract

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.

Authors

Marcel S. Woo, Lukas C. Bal, Ingo Winschel, Elias Manca, Mark Walkenhorst, Bachar Sevgili, Jana K. Sonner, Giovanni Di Liberto, Christina Mayer, Lars Binkle-Ladisch, Nicola Rothammer, Lisa Unger, Lukas Raich, Alexandros Hadjilaou, Barbara Noli, Antonio L. Manai, Vanessa Vieira, Nina Meurs, Ingrid Wagner, Ole Pless, Cristina Cocco, Samuel B. Stephens, Markus Glatzel, Doron Merkler, Manuel A. Friese

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Figure 4

Persistent VGF exposure exacerbates excitotoxicity by inducing glycolysis.

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Persistent VGF exposure exacerbates excitotoxicity by inducing glycolysi...
(A) Relative cell viability (RU, relative units) of neuronal cultures that overexpress EGFP (controls) or VGF and were exposed to glutamate (n = 6 per group). (B) Volcano plot showing all differentially expressed genes (DEGs) between control (EGFP) and VGF-overexpressing neurons. (C) GSEA of all DEG between control (EGFP) and VGF-overexpressing neurons. Size shows number of genes of GO terms, color shows significance. (D) Baseline ATP levels in control (EGFP) and VGF-overexpressing neurons (n = 6 per group). (E and F) Mitochondrial respiration (E) and glycolytic index (F) of control (EGFP) and VGF-overexpressing neurons (n = 6 per group). (G) Glycolytic index of control (mScarlet) and NR4A2-overexpressing neurons (n = 5 per group). (H) Glycolytic index of WT and Vgf-deficient neurons (n = 5 per group). (I) Glycolytic index of WT and Vgf-deficient neurons that overexpress NR4A2 (n = 5 per group). (J) Relative cell viability (RU) VGF-overexpressing neurons that were exposed to glutamate and were pretreated with vehicle (control) or 5 mM 2-DG (n = 5 per group). Data was normalized to controls without glutamate stimulation. (K) Relative cell viability (RU) of neuronal cultures that overexpress mScarlet (control) or NR4A2 and were exposed to glutamate and pretreated with vehicle or 5 mM 2-DG (n = 5 per group). Data was normalized to controls without glutamate stimulation. Points represent individual experiments, additionally, mean is shown. If not stated otherwise, unpaired t test with FDR correction for multiple comparisons was used. *P < 0.05, **P < 0.01, ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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