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Altered neuronal network and rescue in a human MECP2 duplication model
Increased dosage of MeCP2 results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSC) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in hu...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720528/ https://www.ncbi.nlm.nih.gov/pubmed/26347316 http://dx.doi.org/10.1038/mp.2015.128 |
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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 M.B. Bagni, Claudia Ramocki, Melissa B. Araujo, Bruno H. S. Torres, Laila B. Lupski, James R. Van Esch, Hilde Muotri, Alysson R. |
author_facet | Nageshappa, Savitha Carromeu, Cassiano Trujillo, Cleber A. Mesci, Pinar Espuny-Camacho, Ira Pasciuto, Emanuela Vanderhaeghen, Pierre Verfaillie, Catherine Raitano, Susanna Kumar, Anujith Carvalho, Claudia M.B. Bagni, Claudia Ramocki, Melissa B. Araujo, Bruno H. S. Torres, Laila B. Lupski, James R. Van Esch, Hilde Muotri, Alysson R. |
author_sort | Nageshappa, Savitha |
collection | PubMed |
description | Increased dosage of MeCP2 results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSC) 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 increase synaptogenesis and dendritic complexity. Additionally, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 function at the epigenetic level, we tested if 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. |
format | Online Article Text |
id | pubmed-4720528 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-47205282016-05-18 Altered neuronal network and rescue in a human MECP2 duplication model Nageshappa, Savitha Carromeu, Cassiano Trujillo, Cleber A. Mesci, Pinar Espuny-Camacho, Ira Pasciuto, Emanuela Vanderhaeghen, Pierre Verfaillie, Catherine Raitano, Susanna Kumar, Anujith Carvalho, Claudia M.B. Bagni, Claudia Ramocki, Melissa B. Araujo, Bruno H. S. Torres, Laila B. Lupski, James R. Van Esch, Hilde Muotri, Alysson R. Mol Psychiatry Article Increased dosage of MeCP2 results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSC) 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 increase synaptogenesis and dendritic complexity. Additionally, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 function at the epigenetic level, we tested if 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. 2015-09-08 2016-02 /pmc/articles/PMC4720528/ /pubmed/26347316 http://dx.doi.org/10.1038/mp.2015.128 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Nageshappa, Savitha Carromeu, Cassiano Trujillo, Cleber A. Mesci, Pinar Espuny-Camacho, Ira Pasciuto, Emanuela Vanderhaeghen, Pierre Verfaillie, Catherine Raitano, Susanna Kumar, Anujith Carvalho, Claudia M.B. Bagni, Claudia Ramocki, Melissa B. Araujo, Bruno H. S. Torres, Laila B. Lupski, James R. Van Esch, Hilde Muotri, Alysson R. Altered neuronal network and rescue in a human MECP2 duplication model |
title | Altered neuronal network and rescue in a human MECP2 duplication model |
title_full | Altered neuronal network and rescue in a human MECP2 duplication model |
title_fullStr | Altered neuronal network and rescue in a human MECP2 duplication model |
title_full_unstemmed | Altered neuronal network and rescue in a human MECP2 duplication model |
title_short | Altered neuronal network and rescue in a human MECP2 duplication model |
title_sort | altered neuronal network and rescue in a human mecp2 duplication model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720528/ https://www.ncbi.nlm.nih.gov/pubmed/26347316 http://dx.doi.org/10.1038/mp.2015.128 |
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