Glycogen synthase GYS1 overactivation contributes to neurodegenerative disease
The pathogenesis of polyglucosan body (PB) diseases is unclear, and established biomarkers are missing.
The authors show that localized elevation of glycogen chain elongation:branching ratio leads to PB accumulation and disease.
This work shows that overactive glycogen synthase (GYS1), but not metabolic dysregulation or glycogen hyperphosphorylation, contributes to glycogen insolubility and neuroinflammation. Knockout of PTG, an activator of glycogen synthase, in Lafora disease (LD) mouse models shows glycogen hyperphosphorylation to be uncoupled from glycogen insolubility in LD.
Metabolic dysregulation is modest in in situ-fixed brains, uncoupling metabolomic changes from PB formation and neuroinflammation in PB diseases.
Metabolically volatile malto-oligoglucans correlate with disease progression and expression of inflammatory markers in PB disease mouse models.
https://www.embopress.org/doi/full/10.1038/s44318-024-00339-3
