Glycogen Metabolism and Lafora Disease

描述（由申请方提供）：本研究的目的是了解Lafora肌阵挛性癫痫（癫痫，进行性肌阵挛，2型，EPM 2）中分支不良糖原蓄积的分子基础以及磷酸化在糖原正常代谢中的作用。Lafora病的一个一致特征是在神经元、肌肉和其他组织中积累含有异常分支的糖原样聚合物（聚葡聚糖）的Lafora体。糖原是葡萄糖的分支储存聚合物，通常被认为是作为能量储备。约90%的Lafora病病例可归因于编码laforin的EPM 2A基因（一种基于序列位于双特异性蛋白磷酸酶家族中的磷酸酶）或编码malin的EPM 2B基因（一种E3泛素连接酶）的突变。然后，目标部分地减少到了解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小体的形成。我们实验室最近的工作表明，laforin是一种糖原磷酸酶，能够从多糖中释放磷酸盐。此外，我们发现laforin缺陷的小鼠具有磷酸化程度增加的糖原，这在老年小鼠中导致糖原具有严重异常的性质。因此，该提案的一部分旨在更好地理解糖原磷酸化的化学性质及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与糖原相关的代谢酶水平的变化相关，我们计划研究这种观察与聚合物的缺陷积累的关系。无论致病突变是在EPM 2A还是EPM 2B/NHLRC 1基因中，Lafora患者通常具有相似的临床症状。它们都具有Lafora体的特征。如果像我们认为的那样，laforin的主要功能是从糖原中去除磷酸盐，那么对EPM 2B基因和malin功能的分析可以为理解Lafora体形成的机制提供另一种重要的方法。近年来，Malin的作用靶点的确定和Malin功能的研究为Lafora小体的形成和Lafora病的发病机制提供了新的思路。公共卫生相关性：糖原是许多细胞中作为能量储备积累的糖的储存形式，其正常使用模式的破坏与许多疾病有关。神经细胞中糖原的异常使用会导致几种疾病，包括Lafora病，这是一种罕见但致命的癫痫形式。本申请中提出的研究旨在了解Lafora病中糖原储存的问题，这可能有助于为新的治疗方案提供线索。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.