Zhang Longbo, Huang Tianxiang, Teaw Shannon, Nguyen Lena H, Hsieh Lawrence S, Gong Xuan, Burns Lindsay H, Bordey Angélique
Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8082, USA.
Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Street, Changsha, Hunan 410008, China.
Sci Transl Med. 2020 Feb 19;12(531). doi: 10.1126/scitranslmed.aay0289.
Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. In these patients, the presence of focal cortical malformations is associated with the occurrence of lifelong epilepsy, leading to severe neurological comorbidities. Here, we show that the expression of the actin cross-linking protein filamin A (FLNA) is increased in resected cortical tissue that is responsible for seizures in patients with FCDII and in mice modeling TSC and FCDII with mutations in phosphoinositide 3-kinase (PI3K)-ras homolog enriched in brain (Rheb) pathway genes. Normalizing FLNA expression in these mice through genetic knockdown limited cell misplacement and neuronal dysmorphogenesis, two hallmarks of focal cortical malformations. In addition, knockdown reduced seizure frequency independently of mTOR signaling. Treating mice with a small molecule targeting FLNA, PTI-125, before the onset of seizures alleviated neuronal abnormalities and reduced seizure frequency compared to vehicle-treated mice. In addition, the treatment was also effective when injected after seizure onset in juvenile and adult mice. These data suggest that targeting FLNA with either short hairpin RNAs or the small molecule PTI-125 might be effective in reducing seizures in patients with TSC and FCDII bearing mutations in PI3K-Rheb pathway genes.
迫切需要针对患有雷帕霉素作用靶点（mTOR）疾病的患者，如结节性硬化症（TSC）或II型局灶性皮质发育不良（FCDII）的癫痫治疗方法。在这些患者中，局灶性皮质畸形的存在与终身癫痫的发生相关，导致严重的神经合并症。在这里，我们表明，在FCDII患者以及携带磷脂酰肌醇3激酶（PI3K）-富含脑的Ras同源物（Rheb）通路基因突变的TSC和FCDII小鼠模型中，负责癫痫发作的切除皮质组织中肌动蛋白交联蛋白细丝蛋白A（FLNA）的表达增加。通过基因敲低使这些小鼠的FLNA表达正常化，限制了细胞错位和神经元发育异常，这是局灶性皮质畸形的两个标志。此外，敲低独立于mTOR信号传导降低了癫痫发作频率。与用载体处理的小鼠相比，在癫痫发作开始前用靶向FLNA的小分子PTI-125治疗小鼠可减轻神经元异常并降低癫痫发作频率。此外，在幼年和成年小鼠癫痫发作开始后注射该治疗方法也有效。这些数据表明，用短发夹RNA或小分子PTI-125靶向FLNA可能有效地减少携带PI3K-Rheb通路基因突变的TSC和FCDII患者的癫痫发作。
