Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2.
Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2.
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DOI：
10.1007/s13238-020-00773-z
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发表时间：
2021-08
期刊：
影响因子：
21.1
通讯作者：
Sun YE
中科院分区：
文献类型：
--
作者：
Chen X;Han X;Blanchi B;Guan W;Ge W;Yu YC;Sun YE
瑞特综合征（RTT）是一种进行性神经发育障碍，主要由MeCP2基因突变引起，目前无法治愈。我们在此报告，来自R106W MeCP2 RTT人类诱导多能干细胞以及MeCP2敲低后的人类胚胎干细胞的神经元在成熟方面表现出持续且长期的损伤，这表现为动作电位和被动膜特性受损，以及胞体大小和树突棘密度降低。此外，神经元成熟过程中RTT固有的缺陷可能是全神经元性的，并且发生在具有背侧和腹侧前脑特征的神经元中。与RTT诱导多能干细胞衍生的神经元相比，MeCP2的敲低导致更严重的神经元缺陷，而RTT诱导多能干细胞衍生的神经元似乎保留了部分功能。引人注目的是，核大小、树突复杂性以及依赖于回路的自发突触后电流的一致性缺陷仅在MeCP2敲低的神经元中观察到，而在RTT诱导多能干细胞衍生的神经元中未观察到。MeCP2缺陷神经元的神经元内在缺陷和依赖于回路的缺陷都可以通过野生型或T158M MeCP2的重新表达而完全或部分挽救，这加强了MeCP2对疾病表型的剂量依赖性以及突变体的部分功能。因此，我们的研究结果揭示了稳定的神经元成熟缺陷，并且出乎意料的是，神经元固有和神经传递表型对MeCP2缺乏程度的分级敏感性，这对未来的治疗发展具有指导意义。
本文的在线版本（10.1007/s13238 - 020 - 00773 - z）包含补充材料，授权用户可获取。
Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in maturation as indicated by impaired action potentials and passive membrane properties as well as reduced soma size and spine density. Moreover, RTT-inherent defects in neuronal maturation could be pan-neuronal and occurred in neurons with both dorsal and ventral forebrain features. Knockdown of MeCP2 led to more severe neuronal deficits as compared to RTT iPSC-derived neurons, which appeared to retain partial function. Strikingly, consistent deficits in nuclear size, dendritic complexity and circuitry-dependent spontaneous postsynaptic currents could only be observed in MeCP2 knockdown neurons but not RTT iPSC-derived neurons. Both neuron-intrinsic and circuitry-dependent deficits of MeCP2-deficient neurons could be fully or partially rescued by re-expression of wild type or T158M MeCP2, strengthening the dosage dependency of MeCP2 on disease phenotypes and also the partial function of the mutant. Our findings thus reveal stable neuronal maturation deficits and unexpectedly, graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, which is informative for future therapeutic development. The online version of this article (10.1007/s13238-020-00773-z) contains supplementary material, which is available to authorized users.
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作者：
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