Consejo Superior de Investigaciones Científicas, Instituto de Biomedicina de Valencia, Valencia, Spain.
CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Biomedicina de Valencia, Valencia, Spain.
Glia. 2021 May;69(5):1170-1183. doi: 10.1002/glia.23956. Epub 2020 Dec 23.
Lafora disease (LD) is a fatal rare type of progressive myoclonus epilepsy that appears during early adolescence. The disease is caused by mutations in EPM2A or EPM2B genes, which encode laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase, respectively. Although the exact roles of laforin and malin are still not well understood, it is known that they work as a complex in which laforin recruits targets that will be ubiquitinated by malin. Recently, we suggested that the type of epilepsy that accompanies LD could be due to deficiencies in the function of the astrocytic glutamate transporter GLT-1. We described that astrocytes from LD mouse models presented decreased levels of GLT-1 at the plasma membrane, leading to increased levels of glutamate in the brain parenchyma. In this work, we present evidence indicating that in the absence of a functional laforin/malin complex (as in LD cellular models) there is an alteration in the ubiquitination of GLT-1, which could be the cause of the reduction in the levels of GLT-1 at the plasma membrane. On the contrary, overexpression of the laforin/malin complex promotes the retention of GLT-1 at the plasma membrane. This retention may be due to the direct ubiquitination of GLT-1 and/or to an opposite effect of this complex on the dynamics of the Nedd4.2-mediated endocytosis of the transporter. This work, therefore, presents new pieces of evidence on the regulation of GLT-1 by the laforin/malin complex, highlighting its value as a therapeutic target for the amelioration of the type of epilepsy that accompanies LD.
拉佛拉病 (LD) 是一种致命的罕见进行性肌阵挛性癫痫，出现在青少年早期。该疾病由 EPM2A 或 EPM2B 基因突变引起，分别编码葡聚糖磷酸酶 laforin 和 E3 泛素连接酶 malin。尽管 laforin 和 malin 的确切作用仍不清楚，但已知它们作为复合物发挥作用，其中 laforin 招募将被 malin 泛素化的靶标。最近，我们提出 LD 伴发的癫痫类型可能是由于星形胶质细胞谷氨酸转运体 GLT-1 功能缺陷所致。我们描述了 LD 小鼠模型的星形胶质细胞在质膜上 GLT-1 水平降低，导致脑实质中谷氨酸水平升高。在这项工作中，我们提供了证据表明，在缺乏功能性 laforin/malin 复合物的情况下（如 LD 细胞模型中），GLT-1 的泛素化发生改变，这可能是 GLT-1 在质膜水平降低的原因。相反，laforin/malin 复合物的过表达促进 GLT-1 保留在质膜上。这种保留可能是由于 GLT-1 的直接泛素化和/或该复合物对 Nedd4.2 介导的转运体内吞动力学的相反作用。因此，这项工作提供了关于 laforin/malin 复合物对 GLT-1 调节的新证据，突出了其作为改善 LD 伴发癫痫类型的治疗靶点的价值。
