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MEG3 Prevents Cell Death by Restoring Autophagic Flux in Developing Neurons with CLCN4 Variants

ABSTRACT: Variations in CLCN4, encoding the H+/Cl- exchanger CLC-4, are associated with neurodevelopmental disorders, yet their mechanisms remain unclear. To investigate their impact, we introduced patient-relevant CLCN4 variants into human pluripotent stem cells via genome editing and differentiated them into neurons and brain organoids. CLCN4 variants led to a reduction in excitatory neurons due to early-stage neurodegeneration, altering vesicular dynamics in the endo-lysosomal system, disrupting autophagic flux, and increasing neuronal vulnerability. Transcriptomic profiling identified MEG3, a significantly downregulated long non-coding RNA in CLCN4-variant neurons. Restoring MEG3 expression rescued autophagic flux, mitigated lysosomal dysfunction, and improved survival of CLCN4-variant neurons. These findings establish a link between CLCN4 dysfunction, impaired autophagy, and neurodegeneration, highlighting MEG3 as a potential therapeutic target for neurodevelopmental disorders involving autophagy dysfunction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298461 | GEO | 2026/05/29

REPOSITORIES: GEO

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Project description:Background Transforming growth factor β1 (TGF-β1) has a neuroprotective function in traumatic brain injury (TBI) through its anti-inflammatory and immunomodulatory properties. In our previous study, we found that TGF-β1 played a critical role in inhibiting apoptosis and increasing neuronal activity in murine cortical neurons following trauma. However, the precise mechanisms underlying the neuroprotective actions of TGF-β1 on the cortex require further investigation. Methods Thus, in this study, we were aimed to investigate the regulatory function of TGF-β1 on neuronal autophagy and apoptosis using an in vitro primary cortical neuron trauma-injury model. Results To establish the landscape of differentially expressed genes (DEGs) with or without TGF-β1 (10ng/ml) treatment for 24 hours, we performed RNA-sequencing. We observed significant enrichment of DEGs related to autophagy, apoptosis, and the lysosome pathway in trauma-injured cortical neurons. Additionally, transmission electron microscopy (TEM) confirmed the presence of autophagosomes as well as autophagolysosomes. Western blot analysis revealed upregulation of autophagy-related protein light chain 3 (LC3)-Ⅱ/LC3-Ⅰ, sequestosome 1 (SQSTM1)/p62, along with apoptosis-related protein Cleaved-caspase3 in trauma-injured primary cortical neurons. Furthermore, mechanically injured neurons showed an upregulation of lysosomal marker protein lysosomal marker protein (LAMP1) and lysosomal enzyme mature cathepsin D (mCTSD), but a decrease in the activity of CTSD enzyme. These results indicated that apoptosis was up-regulated in mechanically injured neurons at 24 hours, accompanied by lysosomal dysfunction and impaired autophagic flux. Notably, TGF-β1 significantly reversed these changes. Conclusions Therefore, our findings suggested that TGF-β1 exerted neuroprotective effects on mechanically injured neurons by reducing lysosomal dysfunction, decreasing the accumulation of autophagosomes and autophagolysosomes, and enhancing autophagic flux.

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MEG3 Prevents Cell Death by Restoring Autophagic Flux in Developing Neurons with CLCN4 Variants

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