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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Differentiation / physiology
  • Female
  • GABAergic Neurons / metabolism*
  • GABAergic Neurons / physiology*
  • Histone Deacetylase 6 / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / physiology*
  • Male
  • Rett Syndrome / metabolism*
  • Rett Syndrome / physiopathology*
  • Tubulin / metabolism*

Substances

  • Tubulin
  • HDAC6 protein, human
  • Histone Deacetylase 6