Proteomic Analysis After Status Epilepticus Identifies UCHL1 as Protective Against Hippocampal Injury.
Proteomic Analysis After Status Epilepticus Identifies UCHL1 as Protective Against Hippocampal Injury.
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癫痫持续状态后的蛋白质组学分析确定 UCHL1 可预防海马损伤。
DOI：
10.1007/s11064-017-2260-6
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发表时间：
2017
影响因子：
4.4
通讯作者：
Henshall,DavidC
中科院分区：
文献类型：
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作者：
Reynolds,JamesP;Jimenez-Mateos,EvaM;Cao,Li;Bian,Fang;Alves,Mariana;Miller-Delaney,SuzanneF;Zhou,An;Henshall,DavidC
短暂、无害的癫痫发作（预处理）可以暂时保护大脑免受长时间、否则会造成伤害的癫痫发作。在预处理（耐受性）和假预处理（损伤）小鼠的局灶性发作癫痫持续状态（SE）后，我们使用蛋白质组学方法筛选蛋白质变化，并确定了几个癫痫耐受性的假定候选者。在SE诱导的蛋白质组学筛选的变化中，蛋白质聚集在关键的调控途径中，包括蛋白质运输和细胞骨架调控。下调这样一种蛋白质，泛素羧基末端水解酶同工酶L1（UCHL1），是独特的损伤和不明显的耐受性。UCHL1抑制降低海马泛素，破坏UPS功能，干扰癫痫发作终止和加剧癫痫诱导的细胞死亡。尽管SE后UCHL1的转录得以维持，但我们观察到了反义Uchl1（AsUchl1）的下调，并证实AsUchl1和雷帕霉素都能增加UCHL1在体内的表达。这些数据表明，转录后丢失的UCHL1以下SE是有害的神经元的生存，并可能有助于过度兴奋，并提示一种新的雷帕霉素治疗方式。
Brief, non-harmful seizures (preconditioning) can temporarily protect the brain against prolonged, otherwise injurious seizures. Following focal-onsetstatus epilepticus(SE) in preconditioned (tolerance) and sham-preconditioned (injury) mice, we screened for protein changes using a proteomic approach and identified several putative candidates of epileptic tolerance. Among SE-induced changes to both proteomic screens, proteins clustered in key regulatory pathways, including protein trafficking and cytoskeletal regulation. Downregulation of one such protein, ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), was unique to injury and not evident in tolerance. UCHL1 inhibition decreased hippocampal ubiquitin, disrupted UPS function, interfered with seizure termination and exacerbated seizure-induced cell death. Though UCHL1 transcription was maintained after SE, we observed downregulation of the pro-translationalantisense Uchl1(AsUchl1) and confirmed that both AsUchl1and rapamycin can increase UCHL1 expression in vivo. These data indicate that the post-transcriptional loss of UCHL1 following SE is deleterious to neuronal survival and may contribute to hyperexcitability, and are suggestive of a novel modality of rapamycin therapy.