Department of Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Ann Neurol. 2010 Dec;68(6):925-33. doi: 10.1002/ana.22156.
Glycogen, the largest cytosolic macromolecule, acquires solubility, essential to its function, through extreme branching. Lafora bodies are aggregates of polyglucosan, a long, linear, poorly branched, and insoluble form of glycogen. Lafora bodies occupy vast numbers of neuronal dendrites and perikarya in Lafora disease in time-dependent fashion, leading to intractable and fatal progressive myoclonus epilepsy. Lafora disease is caused by deficiency of either the laforin glycogen phosphatase or the malin E3 ubiquitin ligase. The 2 leading hypotheses of Lafora body formation are: (1) increased glycogen synthase activity extends glycogen strands too rapidly to allow adequate branching, resulting in polyglucosans; and (2) increased glycogen phosphate leads to glycogen conformational change, unfolding, precipitation, and conversion to polyglucosan. Recently, it was shown that in the laforin phosphatase-deficient form of Lafora disease, there is no increase in glycogen synthase, but there is a dramatic increase in glycogen phosphate, with subsequent conversion of glycogen to polyglucosan. Here, we determine whether Lafora bodies in the malin ubiquitin ligase-deficient form of the disease are due to increased glycogen synthase or increased glycogen phosphate.
We generated malin-deficient mice and tested the 2 hypotheses.
Malin-deficient mice precisely replicate the pathology of Lafora disease with Lafora body formation in skeletal muscle, liver, and brain, and in the latter in the pathognomonic perikaryal and dendritic locations. Glycogen synthase quantity and activity are unchanged. There is a highly significant increase in glycogen phosphate.
We identify a single common modification, glycogen hyperphosphorylation, as the root cause of Lafora body pathogenesis.
糖原是最大的细胞质大分子，通过极度分支获得其功能所必需的可溶性。拉福拉氏体是聚葡聚糖的聚集体，聚葡聚糖是一种长的、线性的、分支不良的、不溶的糖原形式。拉福拉氏体以时间依赖性方式占据拉福拉病中大量神经元树突和胞体，导致难治性和致命性进行性肌阵挛性癫痫。拉福拉病是由 laforin 糖原磷酸酶或 malin E3 泛素连接酶的缺乏引起的。拉福拉氏体形成的 2 个主要假设是：（1）糖原合酶活性增加会使糖原链过快延长，从而导致分支不足，从而产生聚葡聚糖；（2）增加的糖原磷酸导致糖原构象变化、展开、沉淀和转化为聚葡聚糖。最近，研究表明在 laforin 磷酸酶缺乏型拉福拉病中，糖原合酶没有增加，但糖原磷酸显著增加，随后糖原转化为聚葡聚糖。在这里，我们确定疾病中缺乏 malin 的泛素连接酶的拉福拉氏体是否是由于糖原合酶增加还是糖原磷酸增加引起的。
我们生成了缺乏 malin 的小鼠，并测试了这两个假说。
缺乏 malin 的小鼠精确地复制了拉福拉病的病理学，在骨骼肌、肝脏和大脑中形成了拉福拉氏体，在后一种情况下，在特有的胞体和树突位置形成了拉福拉氏体。糖原合酶的数量和活性没有变化。糖原磷酸显著增加。
我们确定了一种单一的共同修饰，即糖原过度磷酸化，是拉福拉体发病机制的根本原因。
