NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by loss-of-function mutations in the MECP2 gene, resulting in diverse cellular dysfunctions. 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-RNA 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.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-01-28
DOI
https://doi.org/10.1093/nar/gkaf074
Citations
6
Primary Topic
Cancer-related molecular mechanisms research
Type
article
Field-Weighted Citation Impact
5.62

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article

NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome

Manel Esteller, Marta Casado-Peláez, Laura Martinez‐Verbo, Cristina Oliveira-Mateos et al.
6 citations
Nucleic Acids Research
Cancer-related molecular mechanisms research
5.62
article

NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome

Manel Esteller, Marta Casado-Peláez, Laura Martinez‐Verbo, Cristina Oliveira-Mateos, Letícia Ferreira Alves, Fernando Setién, Cecilia D. Velasco, Edilene Siqueira Soares, Sònia Guil, Artur Llobet, Judith Armstrong, Tara Srinivas, Marta Soler, Ariadna Tarrasón
article en
6 citations

Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by loss-of-function mutations in the MECP2 gene, resulting in diverse cellular dysfunctions. 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-RNA 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.

Nucleic Acids ResearchVol. 53(4)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (BR), Institució Catalana de Recerca i Estudis Avançats (ES), Hospital Sant Joan de Déu Barcelona (ES), Neurosciences Institute (US), Instituto de Salud Carlos III (ES), Institut d'Investigació Biomédica de Bellvitge (ES), Josep Carreras Leukaemia Research Institute (ES), Ajuntament de L’Hospitalet (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Institute of Neurobiology (BG), Universitat de Barcelona (ES)
U.S. Department of Veterans Affairs, Fundación Cellex, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, Multiple Sclerosis Society, Generalitat de Catalunya, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Institució Catalana de Recerca i Estudis Avançats, Ministerio de Ciencia e Innovación, Universitat de Barcelona, National Institutes of Health, European Regional Development Fund, Agencia Estatal de Investigación, Ciência sem Fronteiras, National Institute of Mental Health
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Cancer-related molecular mechanisms research
5.62
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