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https://www.arca.fiocruz.br/handle/icict/14854
ALTERED NEURONAL NETWORK AND RESCUE IN A HUMAN MECP2 DUPLICATION MODEL
duplication syndrome
induced pluripotent stem cells
disease modeling
epigenetic drugs
HDAC inhibitors
NCH-51
drug screening
multi-electrode arrays
Author
Nageshappa, Savitha
Carromeu, Cassiano
Trujillo, Cleber A.
Mesci, Pinar
Espuny-Camacho, Ira
Pasciuto, Emanuela
Vanderhaeghen, Pierre
Verfaillie, Catherine
Raitano, Susanna
Kumar, Anujith
Carvalho, Claudia Márcia Benedetto de
Bagni, Claudia
Ramocki, Melissa B.
Araujo, Bruno H. S.
Torres, Laila B.
Lupski, James R.
Esch, Hilde Van
Muotri, Alysson R.
Carromeu, Cassiano
Trujillo, Cleber A.
Mesci, Pinar
Espuny-Camacho, Ira
Pasciuto, Emanuela
Vanderhaeghen, Pierre
Verfaillie, Catherine
Raitano, Susanna
Kumar, Anujith
Carvalho, Claudia Márcia Benedetto de
Bagni, Claudia
Ramocki, Melissa B.
Araujo, Bruno H. S.
Torres, Laila B.
Lupski, James R.
Esch, Hilde Van
Muotri, Alysson R.
Affilliation
Center for Human Genetics. Laboratory for the Genetics of Cognition. KU Leuven, Belgium
University 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. USA
University 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. USA
University 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. USA
Université Libre de Bruxelles. Institut de Recherches en Biologie Humaine et Moléculaire.Brussels, Belgium/ VIB Center for the Biology of Disease. Leuven, Belgium
VIB Center for the Biology of Disease. Leuven, Belgium/KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases. KULeuven, Belgium
Université Libre de Bruxelles. Institut de Recherches en Biologie Humaine et Moléculaire.Brussels, Belgium/ VIB Center for the Biology of Disease. Leuven, Belgium/ WELBIO. Brussels, Belgium
Department of Development and Regeneration. Stem Cell Institute Leuven. KU Leuven Medical School. Cluster Stem Cell Biology and Embryology. Leuven, Belgium
Department of Development and Regeneration. Stem Cell Institute Leuven. KU Leuven Medical School. Cluster Stem Cell Biology and Embryology. Leuven, Belgium
Department 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, India
Baylor 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, Brasil
VIB 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, Italy
Baylor College of Medicine. Department of Pediatrics. Section of Pediatric Neurology and Developmental Neuroscience. Houston, TX, USA
University 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. USA
University 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. USA
Baylor College of Medicine. Department of Molecular and Human Genetics, and Human Genome Sequencing Center.Houston, TX, USA
Center for Human Genetics. Laboratory for the Genetics of Cognition. KU Leuven, Belgium/ University Hospitals Leuven. Center for Human Genetics. Department of Clinical genetics. Leuven, Belgium
University 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. USA
University 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. USA
University 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. USA
University 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. USA
Université Libre de Bruxelles. Institut de Recherches en Biologie Humaine et Moléculaire.Brussels, Belgium/ VIB Center for the Biology of Disease. Leuven, Belgium
VIB Center for the Biology of Disease. Leuven, Belgium/KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases. KULeuven, Belgium
Université Libre de Bruxelles. Institut de Recherches en Biologie Humaine et Moléculaire.Brussels, Belgium/ VIB Center for the Biology of Disease. Leuven, Belgium/ WELBIO. Brussels, Belgium
Department of Development and Regeneration. Stem Cell Institute Leuven. KU Leuven Medical School. Cluster Stem Cell Biology and Embryology. Leuven, Belgium
Department of Development and Regeneration. Stem Cell Institute Leuven. KU Leuven Medical School. Cluster Stem Cell Biology and Embryology. Leuven, Belgium
Department 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, India
Baylor 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, Brasil
VIB 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, Italy
Baylor College of Medicine. Department of Pediatrics. Section of Pediatric Neurology and Developmental Neuroscience. Houston, TX, USA
University 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. USA
University 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. USA
Baylor College of Medicine. Department of Molecular and Human Genetics, and Human Genome Sequencing Center.Houston, TX, USA
Center for Human Genetics. Laboratory for the Genetics of Cognition. KU Leuven, Belgium/ University Hospitals Leuven. Center for Human Genetics. Department of Clinical genetics. Leuven, Belgium
University 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. USA
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.
Keywords
MeCP2duplication syndrome
induced pluripotent stem cells
disease modeling
epigenetic drugs
HDAC inhibitors
NCH-51
drug screening
multi-electrode arrays
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