Glycogen Metabolism and Lafora Disease

糖原代谢和拉福拉病

• 批准号: 7911982
• 负责人: PETER J ROACH
• 金额: $ 7.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911982
• 关键词: Address; Affect; Attention; Cells; Characteristics; Chemistry; Clinical; Defect; Deposition; Disease; Electron Microscopy; Enzymes; Epilepsy; Excision; Family; Genes; Glucans; Glucose; Glycogen; Goals; In Vitro; Iodine; Knockout Mice; Laboratories; Lafora Disease; Lead; Metabolic; Metabolism; Molecular; Morphology; Mus; Muscle; Mutation; Myoclonic Epilepsies; Neurons; Oryctolagus cuniculus; Patients; Pattern; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Polymers; Polysaccharides; Progressive Myoclonic Epilepsies; Property; Protein phosphatase; Proteins; Research; Role; Specificity; Structure; Symptoms; Tissues; Treatment Protocols; Work; base; glycogen metabolism; in vivo; inorganic phosphate; insight; interest; lead phosphate; mouse model; polyglucosan; prevent; public health relevance; sugar; ubiquitin-protein ligase

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.

描述(申请人提供)：这项研究的目的是了解Lafora肌阵挛癫痫(癫痫、进行性肌阵挛、2型，EPM2)中分支不良的糖原积累的分子基础，以及磷酸化在糖原正常代谢中的作用。Lafora病的一个一贯特征是在神经元、肌肉和其他组织中积聚含有异常分支的糖原样聚合物(聚葡聚糖)的Lafora小体。糖原是葡萄糖的一种分支储存聚合物，通常被认为是一种能量储备。大约90%的拉福拉病病例可归因于EPM2A基因或EPM2B基因的突变，EPM2A基因编码拉福林，根据序列属于双特异性蛋白磷酸酶家族，EPM2B基因编码马林，E3泛素连接酶。然后，目标部分归结为了解Laforin和Malin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，拉福林是一种糖原磷酸酶，能够从多糖中释放磷酸盐。此外，我们发现Laforin缺陷的小鼠有磷酸化程度增加的糖原，在老年小鼠中，这会导致具有严重异常性质的糖原。因此，该建议的一部分旨在更好地了解糖原磷酸化的化学及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与糖原相关的代谢酶水平的变化有关，我们计划调查这一观察结果与聚合物缺陷积累的关系。Lafora患者的临床症状基本相似，无论致病突变是在EPM2A还是EPM2B/NHLRC1基因。它们都具有拉福拉小体的特征形态。如果像我们认为的那样，Laforin的主要功能是从糖原中清除磷酸盐，那么对EPM2B基因和Malin功能的分析可以为理解Lafora小体的形成机制提供另一种重要的途径。最近，许多注意力集中在寻找Malin的潜在靶点和了解Malin的功能，这将为Lafora小体形成和Lafora病的机制提供新的见解。与公共卫生相关：糖原是糖的一种储存形式，在许多细胞中作为能量储备积累，其正常使用模式的中断与许多疾病有关。神经细胞中糖原的异常使用会导致几种疾病，包括拉福拉病，这是一种罕见但致命的癫痫形式。这项申请中提出的研究试图了解拉福拉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。