The goal of this study is to understand the molecular basis for the accumulation of poorly branched glycogen in the myoclonic epilepsy of Lafora (epilepsy, progressive myoclonus, type 2, EPM2) and the role of phosphorylation in the normal metabolism of glycogen. A consistent feature of Lafora disease is the accumulation, in neurons, muscle and other tissues, of Lafora bodies which contain an abnormally branched glycogen-like polymer (polyglucosan). Glycogen is a branched storage polymer of glucose that is thought normally to serve as an energy reserve. Some 90% of cases of Lafora disease can be attributed to mutations in the EPM2A gene which encodes laforin, a phosphatase that places in the dual specificity protein phosphatase family based on sequence, or the EPM2B gene which encodes malin, an E3 ubiquitin ligase. The objective then reduces in part to understanding how defects in laforin and malin affect glycogen metabolism and lead to abnormalities in glycogen structure and formation of Lafora bodies. Recent work from our laboratory has indicated that laforin is a glycogen phosphatase, able to release phosphate from the polysaccharide. Furthermore, we found that mice defective in laforin have glycogen with an increased degree of phosphorylation that, in older mice, leads to glycogen with grossly aberrant properties. Part of this proposal therefore is aimed at understanding better the chemistry of glycogen phosphorylation and the mechanism(s) for its introduction into and removal from glycogen. In the mouse model of the disease, the formation of the abnormal glycogen deposits correlates with changes in the level of metabolic enzymes that associate with glycogen and we plan to investigate to what degree this observation relates to the defective accumulation of the polymer. Lafora patients have generally similar clinical symptoms whether the causative mutation is in the EPM2A or EPM2B/NHLRC1 gene. All have the characteristic formation of Lafora bodies. If, as we believe, a primary function of laforin is to remove phosphate from glycogen, then analysis of the EPM2B gene and malin function can provide another important approach to understanding the mechanism of Lafora body formation. Much attention has been directed recently at identifying potential targets of malin and understanding malin function should provide new insight into the mechanism of Lafora body formation and Lafora disease.
Glycogen is a storage form of sugar accumulated as an energy reserve in many cells, and disruption of its normal pattern of usage is associated with a number of diseases. Abnormal glycogen use in nerve cells causes several illnesses, including Lafora disease which is a rare but deadly form of epilepsy. The research proposed in this application seeks to understand what is wrong with glycogen storage in Lafora disease, which could help provide clues to new treatment regimens.
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