Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs.
Exosomes in Epilepsy of Tuberous Sclerosis Complex: Carriers of Pro-Inflammatory MicroRNAs.
复制标题
DOI：
10.3390/ncrna7030040
复制
发表时间：
2021-07-10
期刊：
影响因子：
4.3
通讯作者：
Dombkowski AA
中科院分区：
文献类型：
--
作者：
Cukovic D;Bagla S;Ukasik D;Stemmer PM;Jena BP;Naik AR;Sood S;Asano E;Luat A;Chugani DC;Dombkowski AA
外泌体是一类小的、分泌性细胞外囊泡（EV），最近因其在正常细胞功能、疾病过程中的作用以及作为生物标志物的潜力而受到广泛关注。外泌体作为细胞间信使并携带可以改变受体细胞的基因表达和表型的分子货物。在这里，我们研究了结节性硬化症（TSC）中致癫痫组织分泌的外泌体中 microRNA 货物的变化，TSC 是一种多系统遗传性疾病，包括称为结节的脑部病变。大约 90% 的 TSC 患者患有源自块茎的癫痫发作，并且约 60% 对抗癫痫药物有耐药性。目前尚不清楚为什么有些块茎会引起癫痫发作，而另一些则不会，而且耐药性癫痫的分子基础尚不清楚。据信，神经炎症参与其中，并且这种机制的表征可能是破坏癫痫发作、神经炎症和癫痫易感性增加之间“恶性循环”的关键。我们从致癫痫性和非致癫痫性 TSC 块茎中分离出外泌体，并使用小 RNA 测序鉴定了其 microRNA 货物的差异。我们鉴定了 12 种 microRNA（包括 miR-142-3p、miR-223-3p 和 miR-21-5p），它们在致癫痫块茎中显着增加，并且含有激活 Toll 样受体 (TLR7/8) 的核酸基序，启动神经炎症级联反应。来自致癫痫组织的外泌体引起培养细胞中关键通路的诱导，包括先天免疫信号传导 (TLR)、炎症反应和关键信号传导节点 SQSTM1 (p62) 和 CDKN1A (p21)。体外诱导的基因在致癫痫组织中也显着上调。这些结果为外泌体和非编码RNA货物在癫痫神经炎症级联中的作用提供了新的证据，并可能有助于推进治疗耐药性癫痫的新型生物标志物和治疗方法的开发。
Exosomes are a class of small, secreted extracellular vesicles (EV) that have recently gained considerable attention for their role in normal cellular function, disease processes and potential as biomarkers. Exosomes serve as intercellular messengers and carry molecular cargo that can alter gene expression and the phenotype of recipient cells. Here, we investigated alterations of microRNA cargo in exosomes secreted by epileptogenic tissue in tuberous sclerosis complex (TSC), a multi-system genetic disorder that includes brain lesions known as tubers. Approximately 90% of TSC patients suffer from seizures that originate from tubers, and ~60% are resistant to antiseizure drugs. It is unknown why some tubers cause seizures while others do not, and the molecular basis of drug-resistant epilepsy is not well understood. It is believed that neuroinflammation is involved, and characterization of this mechanism may be key to disrupting the “vicious cycle” between seizures, neuroinflammation, and increased seizure susceptibility. We isolated exosomes from epileptogenic and non-epileptogenic TSC tubers, and we identified differences in their microRNA cargo using small RNA-seq. We identified 12 microRNAs (including miR-142-3p, miR-223-3p and miR-21-5p) that are significantly increased in epileptogenic tubers and contain nucleic acid motifs that activate toll-like receptors (TLR7/8), initiating a neuroinflammatory cascade. Exosomes from epileptogenic tissue caused induction of key pathways in cultured cells, including innate immune signaling (TLR), inflammatory response and key signaling nodes SQSTM1 (p62) and CDKN1A (p21). Genes induced in vitro were also significantly upregulated in epileptogenic tissue. These results provide new evidence on the role of exosomes and non-coding RNA cargo in the neuroinflammatory cascade of epilepsy and may help advance the development of novel biomarkers and therapeutic approaches for the treatment of drug-resistant epilepsy.
登录
查看更多内容
DOI：
10.1073/pnas.1521230113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Kowal, Joanna;Arras, Guillaume;Thery, Clotilde
通讯作者：
Thery, Clotilde
影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
影响因子：
6.7
作者：
Dombkowski, Alan A.;Cukovic, Daniela;Chugani, Diane C.
通讯作者：
Chugani, Diane C.
DOI：
10.1073/pnas.1209414109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Fabbri, Muller;Paone, Alessio;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
DOI：
10.1073/pnas.94.24.13317
发表时间：
1997-11-25
影响因子：
11.1
作者：
Jena, BP;Schneider, SW;Sritharan, KC
通讯作者：
Sritharan, KC