[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Nageshappa, S; KU Leuven, Leuven, Belgium > Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics,
Carromeu, C; University of California San Diego, La Jolla, CA, USA > Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine,
Trujillo; University of California San Diego, La Jolla, CA, USA School of Medicine > Department of Pediatrics/Rady Children's Hospital San Diego
Mesci, P; University of California San Diego, La Jolla, CA, USA School of Medicine > Department of Pediatrics/Rady Children's Hospital San Diego
Espuny Camacho, Ira Mercedes ; Université Libre de Bruxelles, Brussels, Belgium, KU Leuven, Belgium. > Institut de Recherches en Biologie Humaine et Moléculaire, VIB Center for the Biology of Disease
Pasciuto, E; VIB, Leuven, Belgium, KU Leuven, Leuven, Belgium > VIB Center for the Biology of Disease, KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases
Vanderhaeghen, P; Université Libre de Bruxelles, Brussels, Belgium, KU Leuven, Belgium > Institut de Recherches en Biologie Humaine et Moléculaire, VIB Center for the Biology of Disease
Verfaille, CM; KU Leuven Medical School, Leuven, Belgium, VIB, Leuven, Belgium > Department of Development and Regeneration, Cluster Stem Cell Biology and Embryology, Stem Cell Institute Leuven, VIB Center for the Biology of Disease KU Leuven, Center for Human Genetics, Laboratory of Neuronal Communication
Raitano, S; KU Leuven Medical School, Leuven, Belgium, VIB, Leuven, Belgium > Department of Development and Regeneration, Cluster Stem Cell Biology and Embryology, Stem Cell Institute Leuven, VIB Center for the Biology of Disease KU Leuven, Center for Human Genetics, Laboratory of Neuronal Communication
Kumar, A; KU Leuven Medical School, Leuven, Belgium, VIB, Leuven, Belgium > Department of Development and Regeneration, Cluster Stem Cell Biology and Embryology, Stem Cell Institute Leuven, VIB Center for the Biology of Disease KU Leuven, Center for Human Genetics, Laboratory of Neuronal Communication
Carvalho, CM; Baylor College of Medicine, Houston, TX, USA > Department of Molecular and Human Genetics,
Bagni, C; Université Libre de Bruxelles, Brussels, Belgium, KU Leuven, Belgium > Institut de Recherches en Biologie Humaine et Moléculaire, VIB Center for the Biology of Disease
Ramocki, MB; Baylor College of Medicine, Houston, TX, USA > Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics,
Araujo, BH; University of California San Diego, La Jolla, CA, USA School of Medicine > Department of Pediatrics/Rady Children's Hospital San Diego
Torres, LB; University of California San Diego, La Jolla, CA, USA School of Medicine > Department of Pediatrics/Rady Children's Hospital San Diego
Lupski, JR; Baylor College of Medicine, Houston, TX, USA > Human Genome Sequencing Center,
Van Esch, H; KU Leuven, Leuven, Belgium > Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics,
Muotri, AR; University of California San Diego, La Jolla, CA, USA School of Medicine > Department of Pediatrics/Rady Children's Hospital San Diego
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