Abstract
Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 functions at the epigenetic level, we tested whether these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders.
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Acknowledgements
This work was supported by grants from the California Institute for Regenerative Medicine (CIRM) TR2-01814 and TR4-06747, the National Institutes of Health through the NIH Director’s New Innovator Award Program (1-DP2-OD006495-01), R01MH094753, the International Rett Syndrome Foundation (IRSF) and a NARSAD Independent Investigator Grant to ARM. Also supported in part by NINDS grants R01 NS058529 (JRL) and K08 NS062711 (MBR), the Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen (G.0767.13) (HVE) (G.084111N10 to CB) and Fondation Jérôme Lejeune, France (CB, SN, HVE). HVE is a senior clinical investigator of the FWO Vlaanderen. EP has been supported by an FWO aspirant fellowship and by a Methusalem grant (KU Leuven and Flanders government). LBT and BHSA were supported by a fellowship from UNIFESP/EPM-Brazil. We are grateful to Professor Nadif-Kasri for sharing a control iPSC cell line and to the patients and their families who participated in this study.
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Nageshappa, S., Carromeu, C., Trujillo, C. et al. Altered neuronal network and rescue in a human MECP2 duplication model. Mol Psychiatry 21, 178–188 (2016). https://doi.org/10.1038/mp.2015.128
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DOI: https://doi.org/10.1038/mp.2015.128
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