PDF(Pubmed)
Abstract：
Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.
摘要：
皮质畸形，例如局灶性皮质发育不良II型（FCDII）与小儿耐药性癫痫有关，需要进行神经外科手术。FCDII是由PI3K-AKT-mTOR通路基因的合子后突变引起的体细胞镶嵌性结果，在健康的脑组织中产生一个亚组的畸形细胞。在这里，我们显示了从人类手术FCDII脑组织获得的急性皮质切片中的癫痫样活动与畸形神经元密度之间的相关性。我们发现了这些病理细胞中细胞衰老的多重特征，包括p53/p16表达，SASP表达和衰老相关β-半乳糖苷酶活性。我们还表明，在MtorS2215FFCDII临床前小鼠模型中，使用抗衰老药物（达沙替尼/槲皮素）可降低衰老细胞的负荷并降低癫痫发作频率，提供概念证明，感觉疗法可能是控制癫痫发作的有用方法。这些发现为选择性靶向FCDII脑组织中的突变衰老细胞的治疗策略铺平了道路。
