PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease

Abstract

Lafora disease is the most common teenage-onset neurodegenerative disease, the main teenage-onset form of progressive myoclonus epilepsy (PME), and one of the severest epilepsies. Pathologically, a starch-like compound, polyglucosan, accumulates in neuronal cell bodies and overtakes neuronal small processes, mainly dendrites. Polyglucosan formation is catalyzed by glycogen synthase, which is activated through dephosphorylation by glycogen-associated protein phosphatase-1 (PP1). Here we remove PTG, one of the proteins that target PP1 to glycogen, from mice with Lafora disease. This results in near-complete disappearance of polyglucosans and in resolution of neurodegeneration and myoclonic epilepsy. This work discloses an entryway to treating this fatal epilepsy and potentially other glycogen storage diseases.

Protein Degradation and Quality Control in Cells from Laforin and Malin Knockout Mice

“…An uncompromised ER stress response points toward a secondary effect that becomes enhanced under stress. Recent studies by Turnbull et al (44,45), Pederson et al (46), and Duran et al (20) have linked the overaccumulation of abnormal glycogen to the causation of Lafora disease as genetic reduction of the glycogen levels by eliminating either glycogen synthase or PTG in mice rescues not only Lafora body formation but also the neurological symptoms associated with the disease. Thus, the defect in protein clearance in Lafora disease may be secondary to the accumulation of abnormal glycogen and sequestration of cellular proteins in the Lafora bodies.…”

Increased Laforin and Laforin Binding to Glycogen Underlie Lafora Body Formation in Malin-deficient Lafora Disease

“…Ϫ/Ϫ mice were described previously (17,28,30). Mice were killed by cervical dislocation, and tissues were quickly dissected and either frozen immediately in liquid nitrogen or fixed in 10% formalin.…”

“…Large as they are, sizes attained by LB appear to be too small to cause symptoms in liver, muscle, and heart cells, but not in the narrow confines of neuronal dendrites in the brain. By the teenage years, replacement of the cytoplasm of numerous dendrites by LB results in onset and then inexorable worsening of epilepsy and neurodegeneration, leading to death by early adulthood (11,14,15,17). Studies in mice show that glycogen from laforin-deficient tissues is hyperphosphorylated (ϳ1/375 glucoses phosphorylated versus 1/1500 in the wild type), poorly branched, and less soluble and tends to precipitate and aggregate, all of which are reversed by dephosphorylation with laforin (2,3).…”

Phosphorylation prevents polyglucosan transport in Lafora disease

“…In a recent study, preventing polyglucosan formation by downregulating GS in LD mice prevented myoclonus and neurodegeneration, and cured the disease, highlighting the role of polyglucosans. 7 The present study suggests that the epileptogenesis initiated by accumulating polyglucosans occurs in the somatodendritic domain of affected neurons. Downregulating GS would prevent this accumulation, with important therapeutic significance.…”