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bioRxiv · 10.1101/2025.07.16.665078

MEG3 Enhances Survival of Developing Human Neurons with CLCN4-Linked Autophagy Impairment

Kim, D.·Koh, Y.·Jeong, H. S.·Kim, J.·Do, H.·Son, G.·Kim, Y.·Lim, H.-H.·Park, J.-E.·Han, J.
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Abstract

Genetic variations in CLCN4, encoding the H+/Cl- exchanger CLC-4, are associated with human neurodevelopmental disorders with highly variable phenotypes. A lack of physiologically relevant models has hampered molecular understanding of pathogenic mechanisms. We now establish engineered brain organoid and neuronal cell systems to examine impacts of patient-relevant CLCN4 genetic variations. We find that CLCN4 variants reduced excitatory neuron numbers due to early-stage cell death, accompanied by altered endo-lysosomal dynamics and disrupted autophagic flux. Transcriptomic profiling showed significant downregulation of long non-coding RNA MEG3 in CLCN4-variant neurons. Restoring MEG3 expression is sufficient to rescue cellular defects and improve survival of CLCN4-variant neurons. These findings link CLCN4 dysfunction with impaired autophagy and neuronal cell death, highlighting MEG3 as a potential therapeutic target for neurodevelopmental disorders involving autophagic dysfunction.

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Kim, D., Koh, Y., Jeong, H. S., Kim, J., Do, H., Son, G., Kim, Y., Lim, H.-H., Park, J.-E., Han, J.. 2025-07-19. MEG3 Enhances Survival of Developing Human Neurons with CLCN4-Linked Autophagy Impairment. https://doi.org/10.1101/2025.07.16.665078

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