Journal article
The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis
The Journal of clinical investigation, Vol.134(16), e177692
06/18/2024
DOI: 10.1172/JCI177692
PMCID: PMC11324305
PMID: 39145444
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.
Inflammation-induced hyperexcitability triggers the neuronal induction of NR4A2, which promotes multiple sclerosis–related neurodegeneration through increased VGF secretion and enhanced glycolysis.
Details
- Title: Subtitle
- The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis
- Creators
- Marcel S. Woo - Universität HamburgLukas C. Bal - University Medical Center Hamburg-EppendorfIngo Winschel - Universität HamburgElias Manca - Universität HamburgMark Walkenhorst - University Medical Center Hamburg-EppendorfBachar Sevgili - Universität HamburgJana K. Sonner - Universität HamburgGiovanni Di Liberto - University of GenevaChristina Mayer - Universität HamburgLars Binkle-LadischNicola Rothammer - University Medical Center Hamburg-EppendorfLisa Unger - Universität HamburgLukas Raich - Universität HamburgAlexandros Hadjilaou - Universität HamburgBarbara NoliAntonio L. Manai - University of CagliariVanessa Vieira - Universität HamburgNina MeursIngrid Wagner - University of GenevaOle PlessCristina CoccoSamuel B. Stephens - University of IowaMarkus Glatzel - University Medical Center Hamburg-EppendorfDoron Merkler - University of GenevaManuel A. Friese - University Medical Center Hamburg-Eppendorf
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.134(16), e177692
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI177692
- PMID
- 39145444
- PMCID
- PMC11324305
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- V 6.2 / Deutsche Multiple Sklerose Gesellschaft Add-on Stipend / Joachim-Herz-Foundation P1180046 / Gemeinnützige Hertie-Stiftung Memorial Stipend / Else Kröner Fresenius Exzellenzinitiative / Studentische Forschergruppen
- Language
- English
- Date published
- 06/18/2024
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984696782302771
Metrics
10 Record Views