Glycogen synthase GYS1 overactivation contributes to glycogen insolubility and malto-oligoglucan-associated...

Polyglucosans are glycogen molecules with overlong chains, which are hyperphosphorylated in the neurodegenerative Lafora disease (LD). Brain polyglucosan bodies (PBs) cause fatal neurodegenerative diseases including Lafora disease and adult polyglucosan body disease (ABPD), for which treatments, biomarkers, and good understanding of their pathogenesis are currently missing. Mutations in the genes for the phosphatase laforin or the E3 ubiquitin ligase malin can cause LD. By depleting PTG, an activator of the glycogen chain-elongating enzyme glycogen synthase (GYS1), in laforin- and malin-deficient LD mice, we show that abnormal glycogen chain lengths and not hyperphosphorylation underlie polyglucosan formation, and that polyglucosan bodies induce neuroinflammation. We provide evidence indicating that a small pool of overactive GYS1 contributes to glycogen insolubility in LD and APBD. In contrast to previous findings, metabolomics experiments using in situ-fixed brains reveal only modest metabolic changes in laforin-deficient mice. These changes are not replicated in malin-deficient or APBD mice, and are not normalized in rescued LD mice. Finally, we identify a pool of metabolically volatile malto-oligoglucans as a polyglucosan body- and neuroinflammation-associated brain energy source, and promising candidate biomarkers for LD and APBD, including malto-oligoglucans and the neurodegeneration marker CHI3L1/YKL40.