The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis
Standard
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, Jahrgang 134, Nr. 16, e177692, 18.06.2024.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
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 -