The goal of this study is to understand the molecular basis for the myoclonic epilepsy of Lafora (epilepsy, progressive myoclonus, type 2, EPM2) and the role of abnormal glycogen metabolism in the disease. 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, or the EPM2B/NHLRC1 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. We showed that laforin is a glycogen phosphatase and mice defective in laforin have glycogen with an increased degree of phosphorylation that, in older mice, leads to glycogen with grossly aberrant properties. This proposal has four aims: (1) Understanding better the chemistry of glycogen phosphorylation and the mechanism(s) for its introduction into glycogen. Such knowledge is of basic importance to glycogen metabolism and will also inform the design of therapies for the disease, of which none exist to date. (2) Epm2A and EPM2B mutations lead to generally similar phenotypes in patients and mice. It is important to understand better the genetic, physical and mechanistic interactions between laforin and malin. (3) Several studies suggest that laforin and malin mutations cause impaired autophagy which could impact the lysosomal disposal of abnormal glycogen. It is thus important to explore the role of autophagy or related processes in Lafora disease and specifically to ask whether malin is a positive regulator of glycogen disposal by trafficking to the lysosome. (4) Malin biochemically is an E3 ubiquitin ligase. Several potential substrates have been proposed but not all are confirmed by study of malin-/- mice. Therefore, unbiased proteomic analyses will be applied to identification of candidate malin substrates and interacting proteins, which could provide significant new information about the mechanism of malin action.
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 genetic 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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