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ALG13 participates in epileptogenesis via regulation of GABA A receptors in mouse models
Cell Death Discovery ( IF 6.1 ) Pub Date : 2020-09-17 , DOI: 10.1038/s41420-020-00319-6
Junming Huo 1 , Shuanglai Ren 1 , Peng Gao 1, 2 , Ding Wan 1, 2 , Shikuo Rong 1 , Xinxiao Li 1 , Shenhai Liu 1 , Siying Xu 1 , Kuisheng Sun 1 , Baorui Guo 1 , Peng Wang 1 , Baoli Yu 3 , Ji Wu 3, 4 , Feng Wang 1, 2 , Tao Sun 1
Affiliation  

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 (GABAAR)-mediated inhibitory synaptic transmission. Furthermore, treatment with low-dose diazepam (a positive allosteric modulator of GABAA receptors), which enhances GABAAR function, also markedly ameliorates severity of epileptic seizures in ALG13KO mice. Moreover, ALG13 may influenced the expression of GABAARα2 membrane and total protein by changing transcription level of GABAARα2. Furthermore, protein interactions between ALG13 and GABAARα2 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 GABAAR function, and may provide new insight into epilepsy prevention and treatment.



中文翻译:

ALG13 通过调节小鼠模型中的 GABA A 受体参与癫痫发生

ALG13(天冬酰胺连接糖基化 13)在 N 连接糖基化过程中发挥着至关重要的作用。ALG13 基因突变是 I 型先天性糖基化疾病 (CDG-I) 的基础,这是一种罕见的糖基化缺陷人类遗传性疾病。癫痫常见于 I 型糖基化先天性疾病 (CDG-I)。在我们的研究中,我们发现约 20% 的成年 ALG13KO 敲除小鼠表现出自发性癫痫发作,这是在同步视频和颅内脑电图记录中发现的。然而,ALG13 缺陷导致癫痫的机制尚不清楚。全细胞膜片钳记录表明,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显着减少。此外,使用低剂量地西泮(GABA A受体的正变构调节剂)治疗可增强 GABA A R 功能,也可显着改善 ALG13KO 小鼠癫痫发作的严重程度。此外,ALG13可能通过改变GABA A Rα2的转录水平来影响GABA A Rα2膜和总蛋白的表达。此外,在野生型小鼠的皮质中观察到ALG13 和 GABA A Rα2 之间的蛋白质相互作用。总的来说,这些结果揭示了ALG13可能通过调节GABA A R功能参与癫痫的发生,并可能为癫痫的预防和治疗提供新的见解。

更新日期:2020-09-18
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