Altered neuronal network and rescue in a human MECP2 duplication model

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

Altered neuronal network and rescue in a human MECP2 duplication model

Submitted by Nuzia Santos ([email protected]) on 2016-07-13T18:33:59Z No. of bitstreams: 1 ve_Nageshappa_Savitha_Altered_CPqRR_2016.pdf: 973558 bytes, checksum: 36ce1b9b175e435858d7c9a9c623198a (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2016-07-13T18:45:46Z (GMT) No. of bitstreams: 1 ve_Nageshappa_Savitha_Altered_CPqRR_2016.pdf: 973558 bytes, checksum: 36ce1b9b175e435858d7c9a9c623198a (MD5)Made available in DSpace on 2016-07-13T18:45:47Z (GMT). No. of bitstreams: 1 ve_Nageshappa_Savitha_Altered_CPqRR_2016.pdf: 973558 bytes, checksum: 36ce1b9b175e435858d7c9a9c623198a (MD5) Previous issue date: 2016Center for Human Genetics. Laboratory for the Genetics of Cognition. KU Leuven, BelgiumUniversity of California San Diego.School of Medicine. Department of Pediatrics/Rady Children’s Hospital San Diego. Department of Cellular & Molecular Medicine. Stem Cell Program, La Jolla, CA. USAUniversity of California San Diego.School of Medicine. Department of Pediatrics/Rady Children’s Hospital San Diego. Department of Cellular & Molecular Medicine. Stem Cell Program, La Jolla, CA. USAUniversity of California San Diego.School of Medicine. Department of Pediatrics/Rady Children’s Hospital San Diego. Department of Cellular & Molecular Medicine. Stem Cell Program, La Jolla, CA. USAUniversité Libre de Bruxelles. Institut de Recherches en Biologie Humaine et Moléculaire.Brussels, Belgium/ VIB Center for the Biology of Disease. Leuven, BelgiumVIB Center for the Biology of Disease. Leuven, Belgium/KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases. KULeuven, BelgiumUniversité Libre de Bruxelles. Institut de Recherches en Biologie Humaine et Moléculaire.Brussels, Belgium/ VIB Center for the Biology of Disease. Leuven, Belgium/ WELBIO. Brussels, BelgiumDepartment of Development and Regeneration. Stem Cell Institute Leuven. KU Leuven Medical School. Cluster Stem Cell Biology and Embryology. Leuven, BelgiumDepartment of Development and Regeneration. Stem Cell Institute Leuven. KU Leuven Medical School. Cluster Stem Cell Biology and Embryology. Leuven, BelgiumDepartment of Development and Regeneration. Stem Cell Institute Leuven. KU Leuven Medical School. Cluster Stem Cell Biology and Embryology. Leuven, Belgium/Manipal Institute of Regenerative Medicine. Bangalore, IndiaBaylor College of Medicine. Department of Molecular and Human Genetics, and Human Genome Sequencing Center.Houston, TX, USA/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, BrasilVIB Center for the Biology of Disease. Leuven, Belgium/ KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases. KULeuven, Belgium/ University of Rome Tor Vergata. Department of Biomedicine and Prevention. Rome, ItalyBaylor College of Medicine. Department of Pediatrics. Section of Pediatric Neurology and Developmental Neuroscience. Houston, TX, USAUniversity of California San Diego.School of Medicine. Department of Pediatrics/Rady Children’s Hospital San Diego. Department of Cellular & Molecular Medicine. Stem Cell Program, La Jolla, CA. USAUniversity of California San Diego.School of Medicine. Department of Pediatrics/Rady Children’s Hospital San Diego. Department of Cellular & Molecular Medicine. Stem Cell Program, La Jolla, CA. USABaylor College of Medicine. Department of Molecular and Human Genetics, and Human Genome Sequencing Center.Houston, TX, USACenter for Human Genetics. Laboratory for the Genetics of Cognition. KU Leuven, Belgium/ University Hospitals Leuven. Center for Human Genetics. Department of Clinical genetics. Leuven, BelgiumUniversity of California San Diego.School of Medicine. Department of Pediatrics/Rady Children’s Hospital San Diego. Department of Cellular & Molecular Medicine. Stem Cell Program, La Jolla, CA. USAIncreased 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