Mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of a child with Rett syndrome

Biochem Biophys Res Commun. 2018 Apr 15;498(4):898-904. doi: 10.1016/j.bbrc.2018.03.077. Epub 2018 Mar 17.

Abstract

Rett syndrome is an X-linked neurodevelopmental disorder associated with psychomotor impairments, autonomic dysfunctions and autism. Patients with Rett syndrome have loss-of-function mutations in MECP2, the gene encoding methyl-CpG-binding protein 2 (MeCP2). Abnormal biogenic amine signaling and mitochondrial function have been found in patients with Rett syndrome; however, few studies have analyzed the association between these factors. This study investigated the functional relationships between mitochondria and the neuronal differentiation of the MeCP2-deficient stem cells from the exfoliated deciduous teeth of a child with Rett syndrome. An enrolled subject in this study was a 5-year-old girl carrying a large deletion that included the methyl-CpG-binding domain, transcriptional repression domain, and nuclear localization signal of MECP2. Using the single-cell isolation technique, we found that the two populations of MeCP2-expressing and MeCP2-deficient stem cells kept their MECP2 expression profiles throughout the stages of cell proliferation and neuronal differentiation in vitro. Neurite outgrowth and branching were attenuated in MeCP2-deficient dopaminergic neurons. MeCP2-deficient cells showed reduced mitochondrial membrane potential, ATP production, restricted mitochondrial distribution in neurites, and lower expression of a central mitochondrial fission factor, dynamin-related protein 1 than MeCP2-expressing cells. These data indicated that MeCP2-deficiency dysregulates the expression of mitochondrial factors required for the maturation of dopaminergic neurons. This study also provides insight into the pathogenic mechanism underlying dysfunction of the intracerebral dopaminergic signaling pathway in Rett syndrome.

Keywords: Deciduous tooth; Dental pulp stem cell; Dopaminergic neuron; Mitochondrion; Rett syndrome.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Culture Techniques
  • Cell Differentiation
  • Child, Preschool
  • Dental Pulp / pathology
  • Dopaminergic Neurons / pathology*
  • Dopaminergic Neurons / ultrastructure
  • Female
  • Humans
  • Membrane Proteins
  • Methyl-CpG-Binding Protein 2 / deficiency*
  • Methyl-CpG-Binding Protein 2 / genetics
  • Mitochondria / pathology*
  • Mitochondrial Proteins
  • Neurites / pathology
  • Rett Syndrome*
  • Stem Cells / pathology*
  • Tooth, Deciduous / pathology

Substances

  • MECP2 protein, human
  • Membrane Proteins
  • Methyl-CpG-Binding Protein 2
  • Mff protein, human
  • Mitochondrial Proteins