ALG13 participates in epileptogenesis via regulation of GABAA receptors in mouse models
ALG13 participates in epileptogenesis via regulation of GABAA receptors in mouse models
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ALG13 通过调节小鼠模型中的 GABA(A) 受体参与癫痫发生
DOI：
10.1038/s41420-020-00319-6
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发表时间：
2020-09-17
影响因子：
7
通讯作者：
Sun, Tao
中科院分区：
文献类型：
--
作者：
Huo, Junming;Ren, Shuanglai;Sun, Tao
ALG13(天冬酰胺连接的糖基化13)在N连接的糖基化过程中起着关键作用。ALG13基因突变是先天性I型糖基化障碍(CDG-I)的基础，CDG-I是一种罕见的具有糖基化缺陷的人类遗传疾病。癫痫常见于先天性I型糖基化障碍(CDG-I)。在我们的研究中，我们发现大约20%的成年ALG13KO基因敲除小鼠表现出自发性癫痫发作，这是在同时进行的视频和脑电信号记录中发现的。然而，ALG13缺乏导致癫痫的机制尚不清楚。全细胞膜片钳记录显示，ALG13KO小鼠的γ-氨基丁酸A受体(GABA(A)R)介导的抑制性突触传递明显减少。此外，小剂量地西潘(GABA(A)受体的一种正性变构调节剂)的治疗增强了GABA(A)R功能，也显著改善了ALG13KO小鼠癫痫发作的严重程度。此外，ALG13可能通过改变GABA(A)Rα2的转录水平而影响GABA(A)Rα2膜和总蛋白的表达。此外，在野生型小鼠的大脑皮质中观察到了ALG13与GABA(A)Rα2之间的蛋白质相互作用。综上所述，ALG13可能通过调节GABA(A)R功能参与癫痫的发生，为癫痫的防治提供新的思路。
ALG13 (asparagine-linked glycosylation 13) plays crucial roles in the process of N-linked glycosylation. Mutations of the ALG13 gene underlie congenital disorders of glycosylation type I (CDG-I), a rare human genetic disorder with defective glycosylation. Epilepsy is commonly observed in congenital disorders of glycosylation type I (CDG-I). In our study, we found that about 20% of adult ALG13KO knockout mice display spontaneous seizures, which were identified in a simultaneous video and intracranial EEG recording. However, the mechanisms of ALG13 by which deficiency leads to epilepsy are unknown. Whole-cell patch-clamp recordings demonstrated that ALG13KO mice show a marked decrease in gamma-aminobutyric acid A receptor (GABA(A)R)-mediated inhibitory synaptic transmission. Furthermore, treatment with low-dose diazepam (a positive allosteric modulator of GABA(A)receptors), which enhances GABA(A)R function, also markedly ameliorates severity of epileptic seizures in ALG13KO mice. Moreover, ALG13 may influenced the expression of GABA(A)R alpha 2 membrane and total protein by changing transcription level of GABA(A)R alpha 2. Furthermore, protein interactions between ALG13 and GABA(A)R alpha 2 were observed in the cortex of wild-type mice. Overall, these results reveal that ALG13 may be involved in the occurrence of epilepsy through the regulation of GABA(A)R function, and may provide new insight into epilepsy prevention and treatment.