Inhibiting glycogen synthesis prevents lafora disease in a mouse model

Lafora disease (LD) is the major teenage-onset progressive myoclonus epilepsy (PME). Insidious cognitive decline and escalating myoclonic, visual, convulsive, and other seizures follow an initial decade of normal development. Within a few years, seizures are intractable, myoclonic absences are near constant, and a disinhibited dementia has set in. A vegetative state with continuous myoclonus characterizes the final stage and most patients die in status epilepticus before age 301. The neuropathology of LD is characterized by progressive formation and growth of Lafora bodies (LB) in neuronal somata and processes, and by neurodegeneration1. LB are composed of aggregates of a variety of proteins and an abnormal form of glycogen that lacks normal glycogen’s normal branching and spherical structure essential to its solubility. The abnormal glycogen, called polyglucosan, makes up over 70% of a LB2. Whether LB are pathogenic, or a mere epiphenotype, remains uncertain. LD is caused by loss of function of either of two interacting enzymes, malin, a ubiquitin E3 ligase, and laforin, a phosphatase3. Malin regulates the amount of laforin, and laforin regulates glycogen phosphorylation. The latter is essential to normal glycogen structure, through mechanisms that remain poorly defined3–5. Based mostly on cell culture experiments, several additional functions, unrelated to glycogen metabolism, have been tentatively attributed to laforin and malin, including tau kinase dephosphorylation, Wnt signaling regulation, and others6–9. It is possible that loss of one or more of these functions, rather than effects on glycogen metabolism and LB formation, underlie the neurodegeneration and PME of LD. PTG is an adaptor protein that mediates dephosphorylation of the glycogen synthesizing (glycogen synthase; GS) and degrading (glycogen phosphorylase; GP) enzymes by the pleiotropic phosphatase PP1, which activates GS, inactivates GP, and thus increases glycogen production10. We recently hypothesized that, malstructured though they are, polyglucosans are glycogen, and reducing glycogen synthesis might reduce LB formation, which, if LB cause the disease, might prevent LD. As a test of this hypothesis, we removed PTG from the laforin-deficient mouse model of LD (laforin knockout; LKO) by crossing PTG knockout mice with the LD mice. This resulted in drastic reduction of LB and rescued the neurodegeneration of the LD mice11. While these results supported the view that LB are pathogenic, there remained the possibility that PTG has adaptor or other functions outside of glycogen metabolism and that its removal prevented neurodegeneration through pathways unrelated to glycogen metabolism and LB. Furthermore, the study was of short duration and did not assess whether the correction of the neurodegeneration is maintained. To address these two issues, we removed GS itself from LKO mice and found that the absence of glycogen synthesis alone was sufficient to prevent LB formation, neurodegeneration, and seizure susceptibility, and do so long-term.