| Summary: | Lafora disease (LD) is an adolescent-onset autosomal recessive progressive myoclonus epilepsy. The main clinical symptoms of the disease are worsening seizures, neurodegeneration and usually death within ten years. No therapeutics or interventions exist for this devastating disease. Mutations in two genes, EPM2A (laforin) and EPM2B (malin) are causative of more than 90 percent of LD. The pathognomonic sign of LD is the presence of abnormal glycogen which precipitates and accumulates into starch-like masses called Lafora bodies (LB). There are two main hypotheses of LB formation. Glycogen is synthesized through the combined activities of glycogen synthase (GS) and branching enzyme (BE). One hypothesis is that LB form due to an overactivation of GS, causing a misbalance between synthesis and branching. Here, malin and laforin regulate levels of GS and other protein(s) involved in glycogen synthesis and when missing, result in their overaccumulation and thus overactivation of synthesis in relation to branching. The second hypothesis is based on evidence of increased phosphorylation of glycogen in LB. In this hypothesis, glycogen becomes abnormal because of the hyperphosphorylation, causing it to precipitate. Laforin is a glycogen phosphatase, and removes phosphate from glycogen. When missing, as in LD, glycogen becomes hyperphosphorylated and forms LB. A role for malin is less clear in this hypothesis. In this thesis, I identify and characterize a third gene, PRDM8, causing an early onset form of LD in a large consanguineous family. I show that it both interacts with laforin and malin and results in their relocation to the nucleus. I also characterize a laforin-interacting protein, Epm2aip1, finding an important role for this previously uncharacterized protein in glycogen metabolism. Epm2aip1-/- mice exhibit hepatic insulin resistance, decreased hepatic glycogen synthesis, increased liver fat, and resistance against obesity in adulthood. Epm2aip1 associates with glycogen synthase (GS), and its absence impairs the allosteric activation of GS by glucose-6-phosphate. Finally, I find that genetically removing PTG, an activator of GS, from mice with Lafora disease results in near-complete disappearance of LB, and resolution of the neurodegeneration and myoclonic epilepsy. This work has revealed a gateway to the treatment of this devastating and fatal disease.
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