Glycogen Metabolism and Lafora Disease

这项研究的目的是了解低分支糖原在体内积累的分子基础。 Lafora肌阵挛癫痫(癫痫，进行性肌阵挛，2型，EPM2)及其作用 糖原正常代谢中的磷酸化。拉福拉病的一个一贯特征是 在神经元、肌肉和其他组织中，含有异常分支的拉福拉小体积聚 类糖原聚合物(聚葡聚糖)。糖原是葡萄糖的一种分支储存聚合物，被认为 通常作为能源储备。约90%的拉福拉病病例可归因于突变 在编码拉福林的EPM2A基因中，拉福林是一种位于双特异性蛋白中的磷酸酶 基于序列的磷酸酶家族，或编码E3泛素连接酶Malin的EPM2B基因。 然后，目标部分地归结为了解拉福林和马林缺陷如何影响糖原。 并导致糖原结构异常和拉福拉小体的形成。 我们实验室最近的研究表明，拉福林是一种糖原磷酸酶，能够释放 从多糖中提取的磷酸盐。此外，我们还发现，拉福林缺陷的小鼠体内有糖原 一种磷酸化程度的增加，在老年小鼠中，会导致具有严重异常性质的糖原。 因此，这项建议的一部分旨在更好地了解糖原磷酸化和 其引入和去除糖原的机制(S)。在疾病的小鼠模型中， 异常糖原沉积的形成与代谢酶水平的变化有关 与糖原有关，我们计划调查这一观察结果与缺陷患者的关系 聚合物的积累。 Lafora患者的临床症状大致相似，无论致病突变是在EPM2A型还是 EPM2B/NHLRC1基因。它们都具有拉福拉小体的特征形态。如果，就像我们相信的那样，初选 Laforin的功能是从糖原中去除磷酸盐，然后分析EPM2B基因和Malin功能 可以为理解拉福拉小体的形成机制提供另一种重要的途径。大有可为 最近，人们的注意力集中在确定Malin的潜在靶点和了解Malin的功能上 应该为拉福拉小体形成和拉福拉病的机制提供新的见解。

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.