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

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 3

VGF is increased in the CNS and blood of EAE animals and pwMS.

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VGF is increased in the CNS and blood of EAE animals and pwMS. (A) Vgf e...
(A) Vgf expression in relative units (RU) in spinal cords and motoneurons of healthy mice and mice undergoing EAE (data was retrieved from ref. 9; n = 5 per group). (B) VGF protein levels in the spinal cords of healthy mice (n = 14) and mice undergoing EAE 10 days (onset, n = 6), 15 days (acute, n = 5), and 30 days (chronic, n = 5) after immunization. (C) Neuronal VGF MFI in cervical spinal cords of healthy mice and mice undergoing acute and chronic EAE (n = 5 per group). Scale bar: 5 μm. (D) Relative fold change of total VGF in the plasma of healthy mice (n = 6) and mice undergoing EAE 10 days (onset, n = 6), 15 days (acute, n = 5), and 30 days (chronic, n = 6) after immunization. (E) Relative fold change of total VGF in the sera of healthy controls and with pwRRMS (n = 20 per group). Controls were age and sex matched. (F) Relative fold change of total VGF in sera of pwRRMS during stable disease and acute relapse (n = 9). Paired t test was used for statistical comparison. (G) Relative fold change of total VGF in the sera of pwRRMS before and after treatment with natalizumab (n = 6 per group). Paired t test was used for statistical comparison. (H) Neuronal VGF MFI in brain biopsies of noninflammatory CNS disease controls (controls) and pwMS (n = 4 per group). Scale bar: 5 μm. 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, ****P < 0.0001.