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Here, we investigated the role of the long noncoding RNA (lncRNA) NEAT1 in the context of MeCP2 deficiency using human neural cells and RTT patient samples. Through single-cell RNA sequencing and molecular analyses, we found that NEAT1 is markedly downregulated in MECP2 knockout (KO) cells at various stages of neural differentiation. NEAT1 downregulation correlated with aberrant activation of the mTOR pathway, abnormal protein metabolism, and dysregulated autophagy, contributing to the accumulation of protein aggregates and impaired mitochondrial function. Reactivation of NEAT1 in MECP2-KO cells rescued these phenotypes, indicating its critical role downstream of MECP2. Furthermore, direct RNA\u2013RNA interaction was revealed as the key process for NEAT1 influence on autophagy genes, leading to altered subcellular localization of specific autophagy-related messenger RNAs and impaired biogenesis of autophagic complexes. Importantly, NEAT1 restoration rescued the morphological defects observed in MECP2-KO neurons, highlighting its crucial role in neuronal maturation. Overall, our findings elucidate lncRNA NEAT1 as a key mediator of MeCP2 function, regulating essential pathways involved in protein metabolism, autophagy, and neuronal morphology.<\/jats:p>","DOI":"10.1093\/nar\/gkaf074","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T12:26:24Z","timestamp":1738067184000},"source":"Crossref","is-referenced-by-count":9,"title":["NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome"],"prefix":"10.1093","volume":"53","author":[{"given":"Edilene","family":"Siqueira","sequence":"first","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), Genesis of cancer Program , 08916 Badalona, Catalonia ,","place":["Spain"]},{"name":"Conselho Nacional de Desenvolvimento Cientifico e Tecnol\u00f3gico (CNPq) , 70.070-010 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,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Oliveira-Mateos","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), Genesis of cancer Program , 08916 Badalona, Catalonia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Casado-Pelaez","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), Genesis of cancer Program , 08916 Badalona, Catalonia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Martinez-Verbo","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), Genesis of cancer Program , 08916 Badalona, Catalonia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Institut de Recerca Pedi\u00e0trica, Hospital Sant Joan de D\u00e9u , 08950\u00a0 Barcelona , Catalonia ,","place":["Spain"]},{"name":"Servei de Medicina Gen\u00e8tica i Molecular, Hospital Sant Joan de D\u00e9u , 08950\u00a0 Barcelona , Catalonia,\u00a0","place":["Spain"]},{"name":"CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III , 28029\u00a0 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-6093","authenticated-orcid":false,"given":"Manel","family":"Esteller","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), Genesis of cancer Program , 08916 Badalona, Catalonia ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biomedica en Red Cancer (CIBERONC) , 28029\u00a0 Madrid ,","place":["Spain"]},{"name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats (ICREA) , 08010\u00a0 Barcelona , Catalonia ,","place":["Spain"]},{"name":"Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB) , 08907\u00a0 Barcelona , Catalonia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Let\u00edcia\u00a0F","family":"Alves","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), Genesis of cancer Program , 08916 Badalona, Catalonia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Llobet","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Department of Pathology and Experimental Therapy, Institute of Neurosciences, University of Barcelona, 08907 , Catalonia ,","place":["Spain"]},{"name":"L\u2019Hospitalet de Llobregat , Catalonia ,","place":["Spain"]},{"name":"Bellvitge Biomedical Research Institute (IDIBELL), 08907\u00a0L\u2019Hospitalet de Llobregat , Catalonia 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