Department of Neurology, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, 330006, Jiangxi, China.
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing, 400016, China.
Cell Death Dis. 2019 Nov 27;10(12):897. doi: 10.1038/s41419-019-2118-8.
Epilepsy is a serious neurological disease characterized by recurrent unprovoked seizures. The exact etiology of epilepsy is not fully understood. Protrudin is a neural membrane protein and is found to be mutated in hereditary spastic paraplegia that characterized by symptoms like seizures. Here, we reported that the expression of protrudin was downregulated in the temporal neocortex of epileptic patients and in the hippocampus and cortex of pentylenetetrazol and kainic acid-kindled epileptic mouse models. Behavioral and electroencephalogram analyses indicated that overexpression of protrudin in the mouse hippocampus increased the latency of the seizure and decreased the frequency and duration of seizure activity. Using whole-cell patch clamp, overexpression of protrudin in the mouse hippocampus resulted in a reduction in action potential frequency and an increase in gamma-aminobutyric acid (GABA)ergic inhibitory current amplitude. Moreover, western blot analysis showed that the membrane expression of the GABA A receptor β2/3 subunit was also upregulated after protrudin overexpression, and coimmunoprecipitation resulted in a protein-protein interaction between protrudin, GABARβ2/3 and GABA receptor-associated protein in the hippocampus of epileptic mice. These findings suggest that protrudin probably inhibits the occurrence and development of epilepsy through the regulation of GABA receptor-mediated synaptic transmission, and protrudin might be a promising target for the treatment of epilepsy.
癫痫是一种以反复发作、无诱因的癫痫发作为特征的严重神经系统疾病。癫痫的确切病因尚未完全了解。Protrudin 是一种神经膜蛋白，在遗传性痉挛性截瘫中发现存在突变，其特征是癫痫等症状。在这里，我们报告了 Protrudin 在癫痫患者的颞叶皮质以及戊四氮和红藻氨酸致痫性癫痫小鼠模型的海马体和皮质中的表达下调。行为和脑电图分析表明，Protrudin 在小鼠海马体中的过表达增加了癫痫发作的潜伏期，降低了癫痫发作的频率和持续时间。使用全细胞膜片钳技术，Protrudin 在小鼠海马体中的过表达导致动作电位频率降低和γ-氨基丁酸（GABA）能抑制性电流幅度增加。此外，Western blot 分析表明，Protrudin 过表达后 GABA A 受体β2/3 亚基的膜表达也上调，免疫共沉淀结果表明，在癫痫小鼠海马体中 Protrudin、GABARβ2/3 和 GABA 受体相关蛋白之间存在蛋白-蛋白相互作用。这些发现表明，Protrudin 可能通过调节 GABA 受体介导的突触传递来抑制癫痫的发生和发展，并且 Protrudin 可能是治疗癫痫的有前途的靶点。
