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Exp Cell Res. 2018 Jul 15;368(2):225-235. doi: 10.1016/j.yexcr.2018.05.001. Epub 2018 May 4.

iPSC-derived neurons profiling reveals GABAergic circuit disruption and acetylated α-tubulin defect which improves after iHDAC6 treatment in Rett syndrome.

Author information

1
Medical Genetics, University of Siena, Strada delle Scotte 4, 53100, Siena, Italy.
2
NatSynDrugs, Department of Biotechnology, Chemistry and Pharmacy, DoE 2018-2022 University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
3
Department of Medical Biotechnologies, University of Siena, Strada delle Scotte 4, 53100 Siena, Italy.
4
Institute of Neuroscience, National Research Council (CNR), Via Giuseppe Moruzzi, 1, 56124 Pisa, Italy.
5
Institute of Neuroscience, National Research Council (CNR), Via Giuseppe Moruzzi, 1, 56124 Pisa, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA, University of Florence, Viale Gaetano Pieraccini, 6, 50139 Florence, Italy.
6
Yale University, Child Study Center, 230 South Frontage Rd, New Haven, CT 06520, United States.
7
Medical Genetics, University of Siena, Strada delle Scotte 4, 53100, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Viale Mario Bracci 2, 53100 Siena, Italy.
8
Institute of Neuroscience, National Research Council (CNR), Via Giuseppe Moruzzi, 1, 56124 Pisa, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA, University of Florence, Viale Gaetano Pieraccini, 6, 50139 Florence, Italy; BIO@SNS lab, Scuola Normale Superiore, Piazza dei Cavalieri, 7, 56126 Pisa, Italy.
9
Medical Genetics, University of Siena, Strada delle Scotte 4, 53100, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Viale Mario Bracci 2, 53100 Siena, Italy. Electronic address: alessandra.renieri@unisi.it.
10
NatSynDrugs, Department of Biotechnology, Chemistry and Pharmacy, DoE 2018-2022 University of Siena, via Aldo Moro 2, 53100 Siena, Italy. Electronic address: campiani@unisi.it.

Abstract

Mutations in MECP2 gene have been identified in more than 95% of patients with classic Rett syndrome, one of the most common neurodevelopmental disorders in females. Taking advantage of the breakthrough technology of genetic reprogramming, we investigated transcriptome changes in neurons differentiated from induced Pluripotent Stem Cells (iPSCs) derived from patients with different mutations. Profiling by RNA-seq in terminally differentiated neurons revealed a prominent GABAergic circuit disruption along with a perturbation of cytoskeleton dynamics. In particular, in mutated neurons we identified a significant decrease of acetylated α-tubulin which can be reverted by treatment with selective inhibitors of HDAC6, the main α-tubulin deacetylase. These findings contribute to shed light on Rett pathogenic mechanisms and provide hints for the treatment of Rett-associated epileptic behavior as well as for the definition of new therapeutic strategies for Rett syndrome.

KEYWORDS:

GABA; HDAC6; HDAC6 inhibitors; RNA-seq; acetylated α-tubulin; iPSC‐derived neurons

PMID:
29730163
DOI:
10.1016/j.yexcr.2018.05.001
[Indexed for MEDLINE]

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