WOREE是一種與WWOX相關的癲癇性腦病變。患有此病徵的兒童面臨著極高的癲癇風險，通常導致極短的預期壽命，大多數在三歲以前就無法倖存。在以前的研究中，我們已經建立了WWOX和神經退行性疾病之間的關聯，具體而言，我們確定WWOX在第一個WW結構域具有Tyr33磷酸化（pY33-WWOX），具有抑制癌症的功能，並在過表達時可誘導細胞凋亡。相反地，當Ser14被磷酸化時（pS14-WWOX），並不會促進凋亡，而是促進癌症和阿茲海默（AD）。pS14-WWOX存在於癌症和AD腦部病變中。此外，我們之前的研究揭示了一組特定淋巴細胞細胞的潛力，即非T非B spleen HYAL-2+/CD3−/CD19−淋巴細胞（由於是被Zfra肽激活而被稱為Z細胞），他能夠緩解AD相關症狀。此外，我們還發現了一種小型化學物質blebbistatin，能夠激活Z細胞，以WWOX依賴性方式殺死癌細胞，在這項研究中，我們旨在研究blebbistatin通過WWOX激活Z細胞來預防PTZ所誘導的癲癇。當小鼠通過尾靜脈注射blebbistatin後，根據癲癇評分測試觀察到blebbistatin顯著抑制了PTZ誘導的癲癇。PTZ降低了小鼠大腦中WWOX蛋白的總水平，但增加了pS14-WWOX。給小鼠注射blebbistatin會導致Wwox+/+和Wwox+/-小鼠中WWOX的上調和pS14-WWOX的下調。此外，blebbistatin有效減輕了PTZ引起的病理特徵，包括神經毒性、神經元損失和異常神經生長。從機制上來說，blebbistatin激活的Z細胞以WWOX依賴性的方式抑制PTZ所誘導的癲癇。與Wwox+/-小鼠相比，激活的Z細胞在Wwox+/+小鼠中有更好的PTZ的抵抗力。總之，blebbistatin能有效減輕癲癇的發作，部分原因是WWOX的激活以及WWOX依賴性的Z細胞激活，從而抑制PTZ誘導的病理。

WOREE is a WWOX-related epileptic encephalopathy. Children with WWOX-associated epilepsy face an elevated risk of experiencing severe epilepsy, often leading to a tragically short life expectancy, with most not surviving beyond the age of three. In our earlier investigations, we have established an association between WWOX and neurodegenerative diseases. Specifically, we determined WWOX, possessing Tyr33 phosphorylation at the first WW domain (pY33-WWOX), exerts cancer suppression and may induce apoptosis when overexpressed. Conversely, when WWOX is Ser14-phosphorylated, pS14-WWOX is not proapoptotic and promotes the progression of cancer and Alzheimer's disease (AD). pS14-WWOX can be found in the lesions of cancer and AD brains. Furthermore, our previous research unveiled the potential of a specific group of lymphocytes, known as non-T/non-B spleen HYAL-2+/CD3−/CD19− lymphocytes (referred to as Z cells due to activation by Zfra peptide), in alleviating the symptoms associated with AD. Additionally, we have identified a small chemical blebbistatin capable of activating Z cells to kill cancer cells in a WWOX-dependent manner. In this study, we aimed to investigate the potential of blebbistatin in preventing pentylenetetrazol (PTZ)-induced seizure epilepsy by activating Z cells via WWOX activation. When mice received blebbistatin via tail vein injections, these mice became significantly resistant to PTZ-induced seizures, as determined by seizure score testing. PTZ decreased the total levels of WWOX protein but increased pS14-WWOX in the mouse brain. Pre-injection of mice with blebbistatin resulted in the upregulation of WWOX and downregulation of pS14-WWOX in both Wwox+/+ and Wwox+/- mice. Moreover, blebbistatin effectively mitigated the pathological characteristics induced by PTZ, including neurotoxicity, neuronal loss, and abnormal neurogenesis. Mechanistically, blebbistatin-activated Z cells conferred resistance to PTZ-induced seizures in a WWOX-dependent manner. Activated spleen Z cells provided better resistance to PTZ in the wild type Wwox+/+ mice than the heterozygous Wwox+/- mice. In conclusion, blebbistatin effectively mitigates seizures due in part to activation of WWOX along with WWOX-dependent Z cell activation to suppress PTZ-induced pathologies.

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