人類WWOX基因位於染色體常見的易斷裂位點FRA16D並常伴隨頻繁的缺失。近親婚姻的孩童中常有染色體隱性遺傳異常所導致的WWOX基因突變與功能喪失，並發現缺少WWOX基因容易形成癲癇性腦病、頑固性癲癇發作、發育遲緩以及人和動物新生兒的早期死亡。研究中，我們發現小鼠中Wwox基因的定向破壞對藥物戊四氮（PTZ）誘發的癲癇發作具有較高的敏感性，野生Wwox + / +小鼠的最高劑量為40mg / kg，Wwox +/-小鼠的極限值為30mg / kg。短合成肽Zfra（調節細胞凋亡的鋅指狀蛋白）可明顯減輕小鼠的癲癇發作。在組織學檢查中，Zfra防止頂葉皮質和海馬神經元缺失。施打Zfra的小鼠在聽覺皮層和海馬區增加了WWOX的表達並抑制了pS14-WWOX。從機理中，Zfra阻斷了PTZ誘導的小鼠海馬中炎性小膠質細胞和星形膠質細胞的活化。 PTZ強烈誘導在Wwox + / -小鼠中神經炎性細胞因子（如iNOS，COX2，NLRP3和IFN-γ），並被Zfra顯著抑制。此外，Zfra還阻斷了RE1沉默轉錄因子（REST）的表達，該因子是離子通道和神經遞質受體的調節劑，可通過抑制諸如GRIA2，GABRB3和GRIN2B等下游基因來防止癲癇發生。 Zfra在Wwox + / -小鼠中顯著上調了GRIA2。 Zfra通過增加Synapsin-1和Synaptophysin的水平恢復了神經元傳遞。通過共同免疫沉澱（Co-IP），WWOX和REST與CREB-1發生相互作用，而CREB-1在癲癇中起關鍵作用。 Zfra降低了CREB-1與WWOX和REST在小鼠大腦中的結合。另外，我們從3隻C57BL / 6小鼠中分離脾細胞，並處理Zfra以刺激稱為Z細胞的脾細胞活化。通過流式細胞儀細胞分選，分離Z細胞並轉移至Wwox + / +和Wwox + / -小鼠。令人驚訝的是，Wwox + / +小鼠賦予了對PTZ誘發的癲癇發作的抵抗力。總之，我們的觀察結果表明Zfra肽是緩解WWOX缺乏引起的癲癇發作的有效藥物。

Human WWOX gene spans a stretch of 1.1-million DNA bases in the chromosomal common fragile site FRA16D. Loss of function mutations in both alleles of WWOX gene is closely related to autosomal recessive abnormalities in pediatric patients from consanguineous families, including epileptic encephalopathy, intractable seizures, developmental delay and death in human newborns. Here, we report that targeted disruption of Wwox gene in mice caused increased susceptibility to pentylenetetrazol (PTZ)-induced seizures. Compared to wild type mice, lower doses of PTZ are needed to induce seizure in Wwox heterozygous mice, suggesting WWOX confers resistance to seizure. A short synthetic peptide zinc finger like protein that regulates apoptosis (Zfra) significantly reduces PTZ-induced seizure in mice. In histological examination, Zfra prevents neuronal loss from PTZ-induced cell death in the parietal cortex and hippocampus. Mice receiving Zfra have increased WWOX expression and suppressed WWOX phosphorylation at Ser14 in auditory cortex and hippocampal regions. Zfra blocks PTZ-induced activation of inflammatory microglia and astrocytes in the mouse hippocampus. Neuroinflammatory cytokines, including iNOS, COX2, NLRP3 and IFN-γ are induced significantly by PTZ (>50-80%), and are significantly decreased by Zfra in Wwox+/- mice. Also, Zfra blocks the expression of an inflammatory protein RE1-silencing transcription factor (REST). Zfra significantly upregulates GRIA2 in Wwox+/- mice and restores neuronal transmission via increasing the level of Synapsin-1 and Synaptophysin. By co-immunoprecipitation, WWOX and REST physically interact with CREB-1, suggesting their roles in epilepsy. Zfra decreases the binding of CREB-1 with WWOX and REST in the brain. Naïve spleen cells from C57BL/6 mice are treated with Zfra overnight, followed by Z cell purification by cell sorting. Activated Z cells are transferred to Wwox+/+ and Wwox+/- mice via tail vein injections, and shown to conferred resistance to PTZ-induced seizure in Wwox+/+ mice. Together, WWOX protein suppresses seizure, and both Zfra and its-activated Z cells contribute, in part, to mitigate seizure.

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