Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783707030072066048 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8197986 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT alarivalentina histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT scalmanipaolo histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT ajmonepaolafrancesca histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT peregosara histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT avignonesabrina histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT catusiilaria histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT lonatipaolaadele histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT borghimariaorietta histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT finellipalma histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT terragnibenedetta histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT mantegazzamassimo histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT russosilvia histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients AT larizzalidia histonedeacetylaseinhibitorsamelioratemorphologicaldefectsandhypoexcitabilityofipscneuronsfromrubinsteintaybipatients |