Altered neuronal network and rescue in a human MECP2 duplication model.
Altered neuronal network and rescue in a human MECP2 duplication model.
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DOI：
10.1038/mp.2015.128
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发表时间：
2016-02
影响因子：
11
通讯作者：
Muotri AR
中科院分区：
文献类型：
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作者：
Nageshappa S;Carromeu C;Trujillo CA;Mesci P;Espuny-Camacho I;Pasciuto E;Vanderhaeghen P;Verfaillie CM;Raitano S;Kumar A;Carvalho CM;Bagni C;Ramocki MB;Araujo BH;Torres LB;Lupski JR;Van Esch H;Muotri AR
MeCP2 剂量的增加会导致出生时出现的显着神经发育表型。我们从 MECP2 重复综合征 (MECP2dup) 患者身上生成了诱导多能干细胞 (iPSC)，携带不同的重复大小，以研究增加 MeCP2 剂量对人类神经元的影响。我们发现，源自这些不同 MECP2dup iPSC 系的皮质神经元具有增加的突触发生和树突复杂性。此外，使用多电极阵列，我们发现 MECP2dup 衍生的神经元中的神经元网络同步发生了改变。考虑到 MeCP2 在表观遗传水平上的功能，我们使用对表观遗传途径具有明确活性的化合物库测试了这些改变是否可逆。一种组蛋白脱乙酰酶抑制剂 NCH-51 被验证为潜在的临床候选药物。有趣的是，这种化合物以前从未被考虑作为神经系统疾病的治疗替代品。我们的模型概括了人类 MECP2 重复综合征的早期阶段，并代表了一种有前景的细胞工具，可促进严重神经发育障碍的治疗药物筛选。
Increased dosage of MeCP2 results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSC) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increase synaptogenesis and dendritic complexity. Additionally, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 function at the epigenetic level, we tested if these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders.