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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo
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Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo

机译：Laforin是一种糖原磷酸酶，其缺乏会导致体内糖原的磷酸化升高

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Lafora disease is a progressive myoclonus epilepsy with onset typically in the second decade of life and death within 10 years. Lafora bodies, deposits of abnormally branched, insoluble glyco-gen-like polymers, form in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual-specificity protein phosphatase family that additionally contains a glycogen binding domain. The molecular basis for the formation of Lafora bodies is completely unknown. Glycogen, a branched polymer of glucose, contains a small amount of co-valently linked phosphate whose origin and function are obscure. We report here that recombinant laforin is able to release this phosphate in vitro, in a time-dependent reaction with an apparent K_m for glycogen of 4.5 mg/ml. Mutations of laforin that disable the glycogen binding domain also eliminate its ability to dephosphor-ylate glycogen. We have also analyzed glycogen from a mouse model of Lafora disease, Epm2a~(-/-) mice, which develop Lafora bodies in several tissues. Glycogen isolated from these mice had a 40% increase in the covalent phosphate content in liver and a 4-fold elevation in muscle. We propose that excessive phosphorylation of glycogen leads to aberrant branching and Lafora body formation. This study provides a molecular link between an observed biochemical property of laforin and the phenotype of a mouse model of Lafora disease. The results also have important implications for glycogen metabolism generally.
机译：Lafora疾病是一种进行性肌阵挛性癫痫，通常在10年内的生死的第二个十年中发作。 Lafora体是异常分支的不溶性糖原样聚合物的沉积物，形成于神经元，肌肉，肝脏和其他组织中。大约一半的Lafora疾病病例是由编码Laforin的EPM2A基因突变引起的，Laforin是双特异性蛋白质磷酸酶家族的一个成员，另外还含有糖原结合域。 Lafora体形成的分子基础是完全未知的。糖原是葡萄糖的支链聚合物，包含少量共价连接的磷酸盐，其起源和功能不清楚。我们在这里报告重组拉福林能够在体外以时间依赖性反应释放这种磷酸盐，表观K_m为4.5 mg / ml。禁用糖原结合域的laforin突变也消除了其使糖原去磷酸化的能力。我们还分析了来自Lafora疾病的小鼠模型Epm2a〜（-/-）小鼠的糖原，该小鼠模型在多个组织中形成Lafora体。从这些小鼠中分离出的糖原在肝脏中的共价磷酸盐含量增加了40％，在肌肉中升高了4倍。我们提出糖原的过度磷酸化会导致异常分支和Lafora体形成。这项研究提供了观察到的laforin生化特性与Lafora疾病小鼠模型的表型之​​间的分子联系。该结果通常对糖原代谢也具有重要意义。

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