Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
Mol Cell Biol. 2012 Feb;32(3):652-63. doi: 10.1128/MCB.06353-11. Epub 2011 Nov 28.
Lafora disease (LD), an inherited and fatal neurodegenerative disorder, is characterized by increased cellular glycogen content and the formation of abnormally branched glycogen inclusions, called Lafora bodies, in the affected tissues, including neurons. Therefore, laforin phosphatase and malin ubiquitin E3 ligase, the two proteins that are defective in LD, are thought to regulate glycogen synthesis through an unknown mechanism, the defects in which are likely to underlie some of the symptoms of LD. We show here that laforin's subcellular localization is dependent on the cellular glycogen content and that the stability of laforin is determined by the cellular ATP level, the activity of 5'-AMP-activated protein kinase, and the affinity of malin toward laforin. By using cell and animal models, we further show that the laforin-malin complex regulates cellular glucose uptake by modulating the subcellular localization of glucose transporters; loss of malin or laforin resulted in an increased abundance of glucose transporters in the plasma membrane and therefore excessive glucose uptake. Loss of laforin or malin, however, did not affect glycogen catabolism. Thus, the excessive cellular glucose level appears to be the primary trigger for the abnormally higher levels of cellular glycogen seen in LD.
拉佛拉病（LD）是一种遗传性和致命的神经退行性疾病，其特征是细胞糖原含量增加，受影响的组织（包括神经元）中形成异常分支的糖原包涵体，称为拉佛拉体。因此，被认为有缺陷的两种蛋白——laforin 磷酸酶和 malin 泛素 E3 连接酶，通过未知的机制调节糖原合成，其缺陷可能是 LD 一些症状的基础。我们在这里表明，laforin 的亚细胞定位依赖于细胞内的糖原含量，而 laforin 的稳定性由细胞内的 ATP 水平、5'-AMP 激活蛋白激酶的活性和 malin 与 laforin 的亲和力决定。通过使用细胞和动物模型，我们进一步表明 laforin-malin 复合物通过调节葡萄糖转运蛋白的亚细胞定位来调节细胞内的葡萄糖摄取；mali n 或 laforin 的缺失导致质膜中葡萄糖转运蛋白的丰度增加，从而导致过度的葡萄糖摄取。然而，laforin 或 malin 的缺失并不影响糖原分解代谢。因此，异常高的细胞内糖原水平似乎是 LD 中细胞内葡萄糖水平异常升高的主要诱因。
