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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.\n                  <\/jats:p>\n                  <jats:p>\n                    Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in\n                    <jats:italic>Mecp2<\/jats:italic>\n                    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\n                    <jats:italic>Mecp2<\/jats:italic>\n                    knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation.\n                  <\/jats:p>","DOI":"10.1038\/s44321-024-00151-w","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T07:01:37Z","timestamp":1728889297000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4385-5565","authenticated-orcid":false,"given":"Alessandro","family":"Esposito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6832-1906","authenticated-orcid":false,"given":"Tommaso","family":"Seri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Breccia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Indrigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5515-7326","authenticated-orcid":false,"given":"Giuseppina","family":"De Rocco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Nuzzolillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6373-689X","authenticated-orcid":false,"given":"Vanna","family":"Denti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1841-4032","authenticated-orcid":false,"given":"Francesca","family":"Pappacena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Tartaglione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1881-856X","authenticated-orcid":false,"given":"Simone","family":"Serrao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Paglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8766-6555","authenticated-orcid":false,"given":"Luca","family":"Murru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"de Pretis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Cioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0820-3155","authenticated-orcid":false,"given":"Nicoletta","family":"Landsberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9589-4662","authenticated-orcid":false,"given":"Fabrizia Claudia","family":"Guarnieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9373-1133","authenticated-orcid":false,"given":"Michela","family":"Palmieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,14]]},"reference":[{"key":"151_CR1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/13810","volume":"23","author":"RE Amir","year":"1999","unstructured":"Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. 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