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

Abstract

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.

Rubinstein–Taybi Syndrome in a Filipino Infant with a Novel CREBBP Gene Pathogenic Variant

“…Notable therapeutics under study include histone deacetylase inhibitors (HDACi) which are expected to prevent the epigenetic alterations from CBP/p300 acetyltransferase dysfunction [ 2 ]. HDAC inhibitors such as Trichostatin A (TSA) and valproic acid have been used on induced pluripotent stem cell (iPSC)-derived neurons from CREBBP-mutated patients and found to ameliorate the morphological anomalies and electrical activity of young and mature neurons, respectively [ 11 ]. Another potential therapeutic target is CBP/CREBBP activation to specifically target CBP/CREBBP-dependent histone acetylation and transcription.…”

KAT3 mutations impair neural crest migration through EMT regulatorssnai1b andsnai2in Rubinstein Taybi Syndrome

“…The iPSC-derived neural model of Rubinstein Taybi Syndrome has been established to decipher the underlying mechanism of intellectual disability and for screening drugs to rescue the hyperexcitability that is observed in patient-derived neurons (24,25). Yet no RSTS iPSC-derived neural crest model has been generated to investigate the potential impact of CREBBP/EP300 mutation on neural crest of RSTS patients.…”

Chromatin Structure and Dynamics: Focus on Neuronal Differentiation and Pathological Implication

“…Based on a better understanding of the pathophysiological mechanisms leading to these pathologies, new therapeutic perspectives have emerged. HDAC inhibitors have shown promising results in Rubinstein Taybi syndrome, being able to reverse the memory defects in mouse models, and to improve morphological and electrophysiological defects of iNeurons [151,169]. Furthermore, in Kabuki syndrome, defects in H3K4 trimethylation, neurogenesis and memory were normalized by HDAC inhibitor treatment (AR-42) [170].…”