NEAT1-Mediated Regulation in Rett Syndrome
Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the MECP2 gene, resulting in diverse cellular dysfunctions. Here, we investigated the role of the long non-coding RNA 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 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, so that NEAT1 deficiency led to altered subcellular localization of specific autophagy-related mRNAs, including ATG5, ATG16L1, and ATG16L2, and impairing the 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 NEAT1 as a key mediator of MeCP2 function, regulating essential pathways involved in protein metabolism, autophagy, and neuronal morphology. Restoration of NEAT1 levels offers a promising therapeutic strategy for mitigating cellular dysfunctions underlying RTT.