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The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis
- Source :
- Journal of Clinical Investigation. August 15, 2024, Vol. 134 Issue 16
- Publication Year :
- 2024
-
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.<br />Introduction Inflammation-induced neurodegeneration is the principal driver of disease progression and the accumulation of neurological disabilities in people with multiple sclerosis (pwMS) (1, 2), the most prevalent inflammatory disease of [...]
- Subjects :
- Cell death -- Research
Neurons -- Research
Inflammation -- Risk factors -- Development and progression -- Research
Multiple sclerosis -- Risk factors -- Development and progression -- Research
Glutamate -- Research
Amino acids -- Research
Glucose metabolism -- Research
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 134
- Issue :
- 16
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.808510063
- Full Text :
- https://doi.org/10.1172/JCI177692