Glycogen Metabolism and Lafora Disease

本研究的目的是了解在糖尿病患者中低分支糖原积累的分子基础。 Lafora的肌阵挛性癫痫（癫痫，进行性肌阵挛，2型，EPM 2）和 糖原的正常代谢中的磷酸化。Lafora病的一个一致特征是 在神经元、肌肉和其他组织中，Lafora小体的积累， 糖原样聚合物（聚葡聚糖）。糖原是葡萄糖的分支储存聚合物， 通常作为能源储备。大约90%的Lafora病病例可归因于突变 在编码laforin的EPM 2A基因中，laforin是一种磷酸酶， 在一些实施方案中，所述基因是基于序列的磷酸酶家族的基因，或编码malin（一种E3泛素连接酶）的EPM 2B基因。 目标然后部分地减少到了解laforin和malin的缺陷如何影响糖原 代谢并导致糖原结构异常和Lafora小体形成。 我们实验室最近的工作表明，laforin是一种糖原磷酸酶，能够释放 磷酸盐从多糖。此外，我们发现laforin缺陷的小鼠具有糖原， 磷酸化程度的增加，在老年小鼠中，导致糖原具有严重异常的特性。 因此，该提案的一部分旨在更好地理解糖原磷酸化的化学反应， 将其引入糖原和从糖原中去除的机制。在该疾病的小鼠模型中， 异常糖原沉积物的形成与代谢酶水平的变化相关， 我们计划研究这一观察结果在多大程度上与糖原缺陷有关， 聚合物的积累。 Lafora患者具有通常相似的临床症状，无论致病突变是在EPM 2A中还是 EPM 2B/NHLRC 1基因。它们都具有Lafora体的特征。如果，正如我们所相信的， laforin的功能是从糖原中去除磷酸盐，然后分析EPM 2B基因和malin的功能 可以提供另一个重要的途径来了解Lafora体的形成机制。多 最近人们的注意力集中在鉴定malin的潜在靶点和了解malin的功能上 为Lafora体形成和Lafora病的发病机制提供了新的认识。

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.