Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy
Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy
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DOI：
10.1093/hmg/ddi306
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发表时间：
2005-09-15
影响因子：
3.5
通讯作者：
Minassian, BA
中科院分区：
文献类型：
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作者：
Lohi, H;Ianzano, L;Minassian, BA
Lafora进行性肌阵发性癫痫，由laforin或malin缺陷引起，潜伏在认知能力下降的正常青少年中，随后迅速出现顽固性癫痫、痴呆和死亡。病理显示神经变性伴神经原纤维缠结形成和拉福拉体（LBs）。lb是淀粉样多葡聚糖的沉积物，由于糖原合成酶（GS）相对于糖原分支酶活性过度活跃，导致糖原分子分支不足，因此不溶。我们以前做了意想不到的观察，在缺乏聚葡聚糖积累的情况下，去甲糖苷特异性地结合聚葡聚糖。这表明去甲素的作用是在糖原合成过程中检测聚葡聚糖的出现，并启动下调GS的机制。糖原合成酶激酶3 （GSK3）是GS的主要抑制剂。GSK3丝氨酸9位点的去磷酸化激活GSK3，通过多个位点的磷酸化抑制GS。葡萄糖-6-磷酸是一种有效的GS变构活化剂。葡萄糖-6-磷酸水平高时，葡萄糖的量增加，其激活的GS超过任何磷的抑制。在这里，我们发现去甲素是一种GSK3丝氨酸9磷酸酶，因此能够通过GSK3使GS失活。我们还表明，去甲素与malin相互作用，malin是一种结合GS的E3泛素连接酶。我们提出，在多葡聚糖出现的情况下，去甲糖苷引导了两条负反馈通路：聚葡聚糖-去甲糖苷- gsk3 -GS抑制GS活性，聚葡聚糖-去甲糖苷-malin-GS通过蛋白酶体降解去除GS。
Lafora progressive myoclonus epilepsy, caused by defective laforin or malin, insidiously present in normal teenagers with cognitive decline, followed by rapidly intractable epilepsy, dementia and death. Pathology reveals neurodegeneration with neurofibrillary tangle formation and Lafora bodies (LBs). LBs are deposits of starch-like polyglucosans, insufficiently branched and hence insoluble glycogen molecules resulting from glycogen synthase (GS) overactivity relative to glycogen branching enzyme activity. We previously made the unexpected observation that laforin, in the absence of which polyglucosans accumulate, specifically binds polyglucosans. This suggested that laforin's role is to detect polyglucosan appearances during glycogen synthesis and to initiate mechanisms to downregulate GS. Glycogen synthase kinase 3 (GSK3) is the principal inhibitor of GS. Dephosphorylation of GSK3 at Ser 9 activates GSK3 to inhibit GS through phosphorylation at multiple sites. Glucose-6-phosphate is a potent allosteric activator of GS. Glucose-6-phosphate levels are high when the amount of glucose increases and its activation of GS overrides any phospho-inhibition. Here, we show that laforin is a GSK3 Ser 9 phosphatase, and therefore capable of inactivating GS through GSK3. We also show that laforin interacts with malin and that malin is an E3 ubiquitin ligase that binds GS. We propose that laforin, in response to appearance of polyglucosans, directs two negative feedback pathways: polyglucosan-laforin-GSK3-GS to inhibit GS activity and polyglucosan-laforin-malin-GS to remove GS through proteasomal degradation.