4-phenylbutyric acid, metformin, terpin and phenoxyethanol do not reduce Lafora bodies in murine Lafora disease

Abstract

Lafora disease is a fatal neurodegenerative epilepsy that results from the accumulation in the brain of insoluble glycogen aggregates (polyglucosans) into Lafora bodies (LB). It is caused by loss of function mutations in either EPM2A or NHLRC1, encoding the glycogen phosphatase, laforin, and the E3 ubiquitin ligase, malin, respectively. The actions of laforin and malin in glycogen homeostasis are interdependent, deficiency of either leading to dysregulated glycogen synthesis. Several studies have demonstrated that genetic lowering of glycogen synthesis in mouse models of LD is therapeutic, reducing LB, neurodegeneration and behavioral phenotypes. Two FDA-approved drugs, 4-phenylbutyric acid and metformin were recently tested in LD mice and reported to reduce LB accumulation. Glycogen branching enzyme deficiency is a second disease characterized by polyglucosan aggregates.  Two additional compounds, terpin and phenoxyethanol, were recently reported to reduce polyglucosan formation in fibroblasts from mice and humans with this disease. In the present study, we administered the above four compounds to genetic mouse models of LD until 3 months of age.  At sacrifice we found no reduction in polyglucosan and LB accumulation compared to controls.  Our results supplement available data on the above drugs as potential therapies for Lafora disease.