Inhibiting glycogen synthesis prevents Lafora disease in a mouse model

Abstract

Lafora disease (LD) is a fatal progressive myoclonus epilepsy characterized neuropathologically by aggregates of abnormally structured glycogen and proteins (Lafora bodies [LBs]), and neurodegeneration. Whether LBs could be prevented by inhibiting glycogen synthesis and whether they are pathogenic remain uncertain. We genetically eliminated brain glycogen synthesis in LD mice. This resulted in long-term prevention of LB formation, neurodegeneration, and seizure susceptibility. This study establishes that glycogen synthesis is requisite for LB formation and that LBs are pathogenic. It opens a therapeutic window for potential treatments in LD with known and future small molecule inhibitors of glycogen synthesis.

Figure 1

LKO mice lacking GS (DKO mice) have no LB and no gliosis. (A–C) LB in the cerebellum (A), hippocampus (B), and skeletal muscle (C) of LKO mice. (D–F) Corresponding brain regions and muscle in DKO mice. (G–I) GFAP staining in the hippocampus of LKO (G), DKO (H), and WT (I) mice. Note the increase in astrocytes (gliosis) in the LKO mice; DKO mice are similar to WT.

Figure 2

DKO mice do not exhibit the neurodegeneration seen in LKO mice. (A, B) Representative low and high power electron micrographs of a cerebellar Purkinje cell from a WT mouse. Note the smooth linear cell contour and normal synaptic contacts with the cell membrane (arrow). (C, D) Corresponding images from a DKO mouse. Purkinje cells exhibit healthy cytoplasms, smooth linear cell membranes, and normal synaptic contacts similar to WT. (E, F) Purkinje cells from an LKO mouse. Note the darkened amorphous cytoplasms, wrinkled plasma membranes, and disturbed synaptic contacts; asterisk in E indicates a LB. (G) Part of a Purkinje cell from an LKO mouse with multiple surrounding LB (asterisks).

Figure 3

LKO mice exhibit a much more severe epileptic response to kainic acid than WT. DKO mice are similar to WT. n = 3–8 mice per genotype, 20–26 months of age. Data is shown as means ± SEM and significance calculated using an unpaired student’s t-test.