Mechanism of neuroinflammation mediated neurodegeneration in multiple sclerosis

Neuronal proteasomal dysfunction, inflammation and energy depletion are hallmarks of neuroinflammatory and neurodegenerative diseases but the interplay between inflammation, proteasomal dysfunction in maintaining neuronal integrity is not clear. 

This study reveals that the neuronal proteasomal activity is drastically reduced by interferon-induced immunoproteasome subunit, proteasome 20S beta 8 (PSMB8), resulting in accumulation of phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key metabolic regulator.

This leads to neuronal glycolysis, reduced pentose phosphate pathway activity, oxidative injury, and ferroptosis.

The researchers also show that targeting PSMB8 or PFKFB3 protected neurons in vitro and in a mouse model of MS. 

https://www.cell.com/cell/fulltext/S0092-8674(25)00616-6

https://sciencemission.com/neurodegeneration-in-multiple-sclerosis