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

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

In: J CLIN INVEST, Vol. 134, No. 16, e177692, 18.06.2024.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Woo, MS, Bal, LC, Winschel, I, Manca, E, Walkenhorst, M, Sevgili, B, Sonner, JK, Di Liberto, G, Mayer, C, Binkle-Ladisch, L, Rothammer, N, Unger, L, Raich, L, Hadjilaou, A, Noli, B, Manai, AL, Vieira, V, Meurs, N, Wagner, I, Pless, O, Cocco, C, Stephens, SB, Glatzel, M, Merkler, D & Friese, MA 2024, 'The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis', J CLIN INVEST, vol. 134, no. 16, e177692. https://doi.org/10.1172/JCI177692

APA

Woo, M. S., Bal, L. C., Winschel, I., Manca, E., Walkenhorst, M., Sevgili, B., Sonner, J. K., Di Liberto, G., Mayer, C., Binkle-Ladisch, L., Rothammer, N., Unger, L., Raich, L., Hadjilaou, A., Noli, B., Manai, A. L., Vieira, V., Meurs, N., Wagner, I., ... Friese, M. A. (2024). The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis. J CLIN INVEST, 134(16), [e177692]. https://doi.org/10.1172/JCI177692

Vancouver

Woo MS, Bal LC, Winschel I, Manca E, Walkenhorst M, Sevgili B et al. The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis. J CLIN INVEST. 2024 Jun 18;134(16). e177692. https://doi.org/10.1172/JCI177692

Bibtex

@article{32d289cff49c4f2bafa4be7699bae030,
title = "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.",
keywords = "Animals, Glycolysis, Mice, Humans, Neurons/metabolism, Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism, Inflammation/metabolism, Multiple Sclerosis/pathology, Mice, Knockout, Signal Transduction, Male, Neurodegenerative Diseases/metabolism",
author = "Woo, {Marcel S} and Bal, {Lukas C} and Ingo Winschel and Elias Manca and Mark Walkenhorst and Bachar Sevgili and Sonner, {Jana K} and {Di Liberto}, Giovanni and Christina Mayer and Lars Binkle-Ladisch and Nicola Rothammer and Lisa Unger and Lukas Raich and Alexandros Hadjilaou and Barbara Noli and Manai, {Antonio L} and Vanessa Vieira and Nina Meurs and Ingrid Wagner and Ole Pless and Cristina Cocco and Stephens, {Samuel B} and Markus Glatzel and Doron Merkler and Friese, {Manuel A}",
year = "2024",
month = jun,
day = "18",
doi = "10.1172/JCI177692",
language = "English",
volume = "134",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "16",

}

RIS

TY - JOUR

T1 - The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis

AU - Woo, Marcel S

AU - Bal, Lukas C

AU - Winschel, Ingo

AU - Manca, Elias

AU - Walkenhorst, Mark

AU - Sevgili, Bachar

AU - Sonner, Jana K

AU - Di Liberto, Giovanni

AU - Mayer, Christina

AU - Binkle-Ladisch, Lars

AU - Rothammer, Nicola

AU - Unger, Lisa

AU - Raich, Lukas

AU - Hadjilaou, Alexandros

AU - Noli, Barbara

AU - Manai, Antonio L

AU - Vieira, Vanessa

AU - Meurs, Nina

AU - Wagner, Ingrid

AU - Pless, Ole

AU - Cocco, Cristina

AU - Stephens, Samuel B

AU - Glatzel, Markus

AU - Merkler, Doron

AU - Friese, Manuel A

PY - 2024/6/18

Y1 - 2024/6/18

N2 - 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.

AB - 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.

KW - Animals

KW - Glycolysis

KW - Mice

KW - Humans

KW - Neurons/metabolism

KW - Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism

KW - Inflammation/metabolism

KW - Multiple Sclerosis/pathology

KW - Mice, Knockout

KW - Signal Transduction

KW - Male

KW - Neurodegenerative Diseases/metabolism

U2 - 10.1172/JCI177692

DO - 10.1172/JCI177692

M3 - SCORING: Journal article

C2 - 39145444

VL - 134

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 16

M1 - e177692

ER -