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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., 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 [...]

The article presents a study which explores the plasmatic changes for VGF-derived peptides in severe psychiatric disorders. It mentions that study also shows a distinct dysregulation of VGF and increased inflammation in patients with severe mental disorders, and supports the hypothesis that VGF and VGF peptides would be potential psychiatric disease biomarkers.

The article presents a study on how overexpression of human alpha-synuclein induces VGF early changes in both blood and brain of rats. Topics include information on peptides containing the C-terminal end (LHRP) of the rat VGF protein; axon terminals of the substantia nigra (SN) of unilateral 6-hydroxydopamine lesioned; and information on early stage of nigrostriatal neurodegeneration.