Rett syndrome (RTT) is a pervasive neurodevelopmental disorder associated with mutation in MECP2 gene. Despite a well-defined genetic cause, there is a growing consensus that a metabolic component could play a pivotal role in RTT pathophysiology. Indeed, perturbed redox homeostasis and inflammation, i.e. oxinflammation, with mitochondria dysfunction as the central hub between the two phenomena, appear as possible key contributing factors to RTT pathogenesis and its clinical features. While these RTT-related changes have been widely documented by transcriptomic profiling, proteomics studies supporting these evidences are still limited. Here, using primary dermal fibroblasts from control and patients, we perform a large-scale proteomic analysis that, together with data mining approaches, allow us to carry out the first comprehensive characterization of RTT cellular proteome, showing mainly changes in expression of proteins involved in the mitochondrial network. These findings parallel with an altered expression of key mediators of mitochondrial dynamics and mitophagy associated with abnormal mitochondrial morphology. In conclusion, our proteomic analysis confirms the pathological relevance of mitochondrial dysfunction in RTT pathogenesis and progression.

中文翻译：

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蛋白质组学分析揭示了Rett综合征的线粒体改变。

Rett综合征（RTT）是与MECP2基因突变相关的普遍性神经发育障碍。尽管有明确的遗传原因，但越来越多的共识是，代谢成分可能在RTT病理生理中起关键作用。确实，扰动的氧化还原稳态和炎症，即线粒体功能紊乱是这两种现象之间的中心枢纽，是炎症性炎症，可能是导致RTT发病机理及其临床特征的关键因素。尽管转录组分析已广泛记录了这些与RTT相关的变化，但支持这些证据的蛋白质组学研究仍然有限。在这里，我们使用对照和患者的原代皮肤成纤维细胞，进行了大规模的蛋白质组学分析，并结合了数据挖掘方法，使我们能够进行RTT细胞蛋白质组的第一个全面表征，主要显示参与线粒体网络的蛋白质表达的变化。这些发现与与异常线粒体形态有关的线粒体动力学和线粒体关键介质表达的改变平行。总之，我们的蛋白质组学分析证实了线粒体功能障碍在RTT发病机理和进展中的病理相关性。