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Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients

Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities...

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Autores principales: Alari, Valentina, Scalmani, Paolo, Ajmone, Paola Francesca, Perego, Sara, Avignone, Sabrina, Catusi, Ilaria, Lonati, Paola Adele, Borghi, Maria Orietta, Finelli, Palma, Terragni, Benedetta, Mantegazza, Massimo, Russo, Silvia, Larizza, Lidia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197986/
https://www.ncbi.nlm.nih.gov/pubmed/34071322
http://dx.doi.org/10.3390/ijms22115777
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author Alari, Valentina
Scalmani, Paolo
Ajmone, Paola Francesca
Perego, Sara
Avignone, Sabrina
Catusi, Ilaria
Lonati, Paola Adele
Borghi, Maria Orietta
Finelli, Palma
Terragni, Benedetta
Mantegazza, Massimo
Russo, Silvia
Larizza, Lidia
author_facet Alari, Valentina
Scalmani, Paolo
Ajmone, Paola Francesca
Perego, Sara
Avignone, Sabrina
Catusi, Ilaria
Lonati, Paola Adele
Borghi, Maria Orietta
Finelli, Palma
Terragni, Benedetta
Mantegazza, Massimo
Russo, Silvia
Larizza, Lidia
author_sort Alari, Valentina
collection PubMed
description Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 CREBBP-mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients’ iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.2 nM, in parallel to neural progenitors from controls. Immunofluorescence of MAP2/TUJ1 positive cells using the Skeletonize Image J plugin evidenced that TSA partially rescued reduced nuclear area, and decreased branch length and abnormal end points number of both 45 days patients’ neurons, but did not influence the diminished percentage of their neurons with respect to controls. Patch clamp recordings of TSA-treated post-mitotic P149 neurons showed complete/partial rescue of sodium/potassium currents and significant enhancement of neuron excitability compared to untreated replicas. Correction of abnormalities of P149 young neurons was also affected by valproic acid 1 mM for 72 h, with some variation, with respect to TSA, on the morphological parameter. These findings hold promise for development of an epigenetic therapy to attenuate RSTS patients cognitive impairment.
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spelling pubmed-81979862021-06-14 Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients Alari, Valentina Scalmani, Paolo Ajmone, Paola Francesca Perego, Sara Avignone, Sabrina Catusi, Ilaria Lonati, Paola Adele Borghi, Maria Orietta Finelli, Palma Terragni, Benedetta Mantegazza, Massimo Russo, Silvia Larizza, Lidia Int J Mol Sci Article Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 CREBBP-mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients’ iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.2 nM, in parallel to neural progenitors from controls. Immunofluorescence of MAP2/TUJ1 positive cells using the Skeletonize Image J plugin evidenced that TSA partially rescued reduced nuclear area, and decreased branch length and abnormal end points number of both 45 days patients’ neurons, but did not influence the diminished percentage of their neurons with respect to controls. Patch clamp recordings of TSA-treated post-mitotic P149 neurons showed complete/partial rescue of sodium/potassium currents and significant enhancement of neuron excitability compared to untreated replicas. Correction of abnormalities of P149 young neurons was also affected by valproic acid 1 mM for 72 h, with some variation, with respect to TSA, on the morphological parameter. These findings hold promise for development of an epigenetic therapy to attenuate RSTS patients cognitive impairment. MDPI 2021-05-28 /pmc/articles/PMC8197986/ /pubmed/34071322 http://dx.doi.org/10.3390/ijms22115777 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alari, Valentina
Scalmani, Paolo
Ajmone, Paola Francesca
Perego, Sara
Avignone, Sabrina
Catusi, Ilaria
Lonati, Paola Adele
Borghi, Maria Orietta
Finelli, Palma
Terragni, Benedetta
Mantegazza, Massimo
Russo, Silvia
Larizza, Lidia
Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients
title Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients
title_full Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients
title_fullStr Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients
title_full_unstemmed Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients
title_short Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients
title_sort histone deacetylase inhibitors ameliorate morphological defects and hypoexcitability of ipsc-neurons from rubinstein-taybi patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197986/
https://www.ncbi.nlm.nih.gov/pubmed/34071322
http://dx.doi.org/10.3390/ijms22115777
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