Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models

Autophagosome biogenesis is impaired in Rett syndrome, a complex neurodevelopmental disorder caused by loss of function mutations in MECP2. Autophagy enhancement restores defects in neurons lacking Mecp2, suggesting a possible contribution of this pathway in the pathogenesis of Rett. (Figure presented.) © The Author(s) 2024.. (Figure presented.) Autophagosome biogenesis is impaired in Rett syndrome, a complex neurodevelopmental disorder caused by loss of function mutations in MECP2. Autophagy enhancement restores defects in neurons lacking Mecp2, suggesting a possible contribution of this pathway in the pathogenesis of Rett. LC3B-II lipidation, which is essential for autophagosome biogenesis, is defective in Mecp2 KO cells, probably due to the reduced availability of phosphatidylethanolamine (PE). The natural disaccharide and autophagy inducer trehalose restores the amount of PE and improves dendritic complexity and synaptic ultrastructure in Mecp2 KO neurons. In vivo administration of trehalose ameliorates exploratory and locomotor skills of Mecp2 KO male mice. © The Author(s) 2024. 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.