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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.
Afiliação
  • Alari V; Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy.
  • Scalmani P; Department of Neurophysiology and Diagnostic Epileptology, IRCCS Foundation C. Besta Neurological Institute, 20133 Milan, Italy.
  • Ajmone PF; Child and Adolescent Neuropsychiatric Service (UONPIA), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy.
  • Perego S; Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy.
  • Avignone S; Department of Neuroradiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
  • Catusi I; Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy.
  • Lonati PA; Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
  • Borghi MO; Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
  • Finelli P; Immunorheumatology Research Laboratory, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy.
  • Terragni B; Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy.
  • Mantegazza M; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy.
  • Russo S; Department of Neurophysiology and Diagnostic Epileptology, IRCCS Foundation C. Besta Neurological Institute, 20133 Milan, Italy.
  • Larizza L; Department of Neurophysiology and Diagnostic Epileptology, IRCCS Foundation C. Besta Neurological Institute, 20133 Milan, Italy.
Int J Mol Sci ; 22(11)2021 May 28.
Article em En | MEDLINE | ID: mdl-34071322
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes Induzidas / Inibidores de Histona Desacetilases / Ácidos Hidroxâmicos / Neurônios Limite: Adolescent / Child / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes Induzidas / Inibidores de Histona Desacetilases / Ácidos Hidroxâmicos / Neurônios Limite: Adolescent / Child / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article