Loss-of-function mutations in MECP2 are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MeCP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways might contribute to neuropathogenesis. Along this line, autophagy is critical in sustaining developing neuron homeostasis by breaking down dysfunctional proteins, lipids, and organelles.Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in Mecp2 knock-out neurons. This correlates with defective lipidation of LC3B, probably caused by a deficiency of the autophagic membrane lipid phosphatidylethanolamine. The administration of the autophagy inducer trehalose recovers LC3B lipidation, autophagosomes content in knock-out neurons, and ameliorates their morphology, neuronal activity and synaptic ultrastructure. Moreover, we provide evidence for attenuation of motor and exploratory impairment in Mecp2 knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation.

中文翻译：

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揭示 Mecp2 缺陷模型中的自噬失衡和治疗见解。


MECP2 功能丧失突变与雷特综合征 （RTT） 有关，RTT 是一种严重的神经发育疾病。MeCP2 主要作为转录调节因子，缺失导致基因表达扰动，导致突触功能和神经元活性缺陷。此外，RTT 患者和小鼠模型患有复杂的代谢综合征，表明相关的细胞通路可能有助于神经发病机制。沿着这条路线，自噬通过分解功能失调的蛋白质、脂质和细胞器来维持发育中的神经元稳态至关重要。在这里，我们研究了 RTT 中的自噬途径，发现 Mecp2 敲除神经元中自噬液泡的含量降低。这与 LC3B 的脂质化缺陷有关，可能是由自噬膜脂质磷脂酰乙醇胺的缺陷引起的。自噬诱导剂海藻糖的施用可恢复 LC3B 脂质、敲除神经元中的自噬体含量，并改善其形态、神经元活性和突触超微结构。此外，我们提供了海藻糖给药后 Mecp2 敲除小鼠运动和探查障碍减弱的证据。总体而言，我们的研究结果为基于自噬调节概念的神经发育障碍治疗开辟了新的前景。