Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury
Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury
复制标题
癫痫持续状态后泛素-蛋白酶体系统抑制的时空进程提示对海马损伤的保护性适应
DOI：
10.1186/s13024-017-0163-2
复制
发表时间：
2017-02-24
影响因子：
15.1
通讯作者：
Henshall, David C.
中科院分区：
文献类型：
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作者：
Engel, Tobias;Martinez-Villarreal, Jaime;Henshall, David C.
背景资料：泛素-蛋白酶体系统（UPS）是导致不需要的和/或错误折叠的可溶性蛋白质降解的主要细胞内途径。这包括调节细胞存活、突触可塑性和神经递质信号传导的蛋白质;控制兴奋性阈值的过程被致癫痫损伤改变。UPS的功能障碍已被报道以脑区域和细胞特异性方式发生，并有助于急性和慢性脑疾病的疾病进展。长时间的癫痫发作，癫痫持续状态，可能会改变UPS功能，但一直没有系统的尝试，映射何时何地发生在体内或确定的后果蛋白酶体抑制对癫痫引起的brain injury.Method：为了确定是否癫痫发作导致UPS的损害，我们使用了癫痫持续状态的小鼠模型，其中癫痫发作是由杏仁核内注射红藻氨酸引发的。在该模型中，癫痫持续状态导致选定脑区的细胞死亡，特别是海马体的同侧CA 3子区，以及在短潜伏期后癫痫的发展。为了监测糖尿病诱导的UPS功能障碍，我们使用了表达泛素融合降解底物泛素（G76 V）-绿色荧光蛋白的UPS抑制报告小鼠。治疗与特定的蛋白酶体抑制剂epoxomicin被用来建立的蛋白酶体抑制的影响，对癫痫引起的pathology.Results和conclusions：我们的研究表明，癫痫持续状态引起的杏仁核内红藻氨酸选择时空UPS抑制，这是最明显的抗损伤区域的海马，包括CA 1锥体和齿状颗粒神经元，然后出现在星形胶质细胞。为了支持这一有益作用，在模型中，给小鼠注射蛋白酶体抑制剂环氧霉素保护了正常脆弱的海马CA 3区免于癫痫诱导的神经元死亡。这些研究揭示了癫痫发作后发生的脑区域和细胞特异性UPS损伤，并表明UPS抑制可以防止癫痫引起的脑损伤。识别癫痫发作后通过蛋白酶体调控的网络或途径可能会产生新的靶基因，用于治疗癫痫引起的细胞死亡和可能的癫痫。
Background: The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of unwanted and/or misfolded soluble proteins. This includes proteins regulating cellular survival, synaptic plasticity and neurotransmitter signaling; processes controlling excitability thresholds that are altered by epileptogenic insults. Dysfunction of the UPS has been reported to occur in a brain region-and cell-specific manner and contribute to disease progression in acute and chronic brain diseases. Prolonged seizures, status epilepticus, may alter UPS function but there has been no systematic attempt to map when and where this occurs in vivo or to determine the consequences of proteasome inhibition on seizure-induced brain injury.Method: To determine whether seizures lead to an impairment of the UPS, we used a mouse model of status epilepticus whereby seizures are triggered by an intra-amygdala injection of kainic acid. Status epilepticus in this model causes cell death in selected brain areas, in particular the ipsilateral CA3 subfield of the hippocampus, and the development of epilepsy after a short latent period. To monitor seizure-induced dysfunction of the UPS we used a UPS inhibition reporter mouse expressing the ubiquitin fusion degradation substrate ubiquitin(G76V)-green fluorescent protein. Treatment with the specific proteasome inhibitor epoxomicin was used to establish the impact of proteasome inhibition on seizure-induced pathology.Results and conclusions: Our studies show that status epilepticus induced by intra-amygdala kainic acid causes select spatio-temporal UPS inhibition which is most evident in damage-resistant regions of the hippocampus, including CA1 pyramidal and dentate granule neurons then appears later in astrocytes. In support of this exerting a beneficial effect, injection of mice with the proteasome inhibitor epoxomicin protected the normally vulnerable hippocampal CA3 subfield from seizure-induced neuronal death in the model. These studies reveal brain region-and cell-specific UPS impairment occurs after seizures and suggest UPS inhibition can protect against seizure-induced brain damage. Identifying networks or pathways regulated through the proteasome after seizures may yield novel target genes for the treatment of seizure-induced cell death and possibly epilepsy.