CNS neuroscience & therapeutics · 2025
Cx47 Phosphorylation Exacerbates White Matter Damage and Kainic Acid Induced Epilepsy.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Li Yi, Lin Haohan, Liu Jiayu, Chen Jie, Shen Kaifeng, Chen Ningning, Xiang Songyang, Wang Duan, Xiao Nong, Li Tingsong
Аннотация
AIMS: Growing evidence implicates dysfunctional myelin in the pathogenesis of temporal lobe epilepsy (TLE). Connexin 47 (Cx47), an oligodendrocytic gap junction protein, maintains myelin integrity. This study investigates the role of Cx47 in myelin impairment and seizure progression in TLE.
METHODS: Cx47 and phosphorylated Cx47 (p-Cx47) expression was analyzed in human and mouse TLE brain tissues via Western blot and immunofluorescence. Candidate Cx47 phosphorylation kinases revealed by single-cell RNA sequencing were validated through immunofluorescence, protein docking, and co-immunoprecipitation. TLE mice were treated with the CaMKII inhibitor KN93 to evaluate its effects on demyelination and seizure burden.
RESULTS: In a experimental mouse model, phosphorylated Cx47 (p-Cx47) was significantly upregulated, recapitulating a similar trend observed in human TLE tissues. This upregulation was accompanied by marked demyelination in the TLE animals. In mice, increased levels of Cx47 and p-Cx47 were associated with elevated CaMKII and phosphorylated CaMKII (p-CaMKII). The interaction between Cx47 and CaMKII was further confirmed. Moreover, administration of KN93 suppressed the upregulation of Cx47 and p-Cx47, thereby mitigating demyelination and reducing seizure progression.
CONCLUSIONS: CaMKII-mediated Cx47 expression and phosphorylation promote demyelination and seizure progression in TLE. Targeting Cx47 phosphorylation may offer a therapeutic strategy for TLE.
METHODS: Cx47 and phosphorylated Cx47 (p-Cx47) expression was analyzed in human and mouse TLE brain tissues via Western blot and immunofluorescence. Candidate Cx47 phosphorylation kinases revealed by single-cell RNA sequencing were validated through immunofluorescence, protein docking, and co-immunoprecipitation. TLE mice were treated with the CaMKII inhibitor KN93 to evaluate its effects on demyelination and seizure burden.
RESULTS: In a experimental mouse model, phosphorylated Cx47 (p-Cx47) was significantly upregulated, recapitulating a similar trend observed in human TLE tissues. This upregulation was accompanied by marked demyelination in the TLE animals. In mice, increased levels of Cx47 and p-Cx47 were associated with elevated CaMKII and phosphorylated CaMKII (p-CaMKII). The interaction between Cx47 and CaMKII was further confirmed. Moreover, administration of KN93 suppressed the upregulation of Cx47 and p-Cx47, thereby mitigating demyelination and reducing seizure progression.
CONCLUSIONS: CaMKII-mediated Cx47 expression and phosphorylation promote demyelination and seizure progression in TLE. Targeting Cx47 phosphorylation may offer a therapeutic strategy for TLE.