Novel aberrant genetic and epigenetic events in Friedreich's ataxia

Exp Cell Res. 2015 Jul 1;335(1):51-61. doi: 10.1016/j.yexcr.2015.04.013. Epub 2015 Apr 28.


It is generally accepted that Friedreich's ataxia (FRDA) is caused by a deficiency in frataxin expression, a mitochondrial protein involved in iron homeostasis, which mainly affects the brain, dorsal root ganglia of the spinal cord, heart and in certain cases the pancreas. However, there is little knowledge as to other possible genes that may be affected in this disorder, and which can contribute to its complexity. In the current study we compared human periodontal ligament cells gene expression of healthy individuals and FRDA patients. The expression of active-caspase 3, as well as other apoptosis-related genes, was increased in the FRDA cells. Furthermore, iron-sulphur cluster genes, as well as oxidative stress-related genes were overexpressed in FRDA. Moreover, brain-derived neurotrophic factor, neuregulin 1 and miR-132 were all upregulated. These three genes are capable of regulating the expression of each other. Interestingly, when the cells from FRDA patients were co-cultured in the presence of idebenone and deferiprone, caspase expression decreased while antioxidant gene expression, as well as frataxin expression, increased. Regarding epigenetic mechanisms, the frataxin gene was hypermethylated, compared to the healthy counterparts, in the upstream GAA repetitive region. Of the three DNA methyltransferases, DNMT1 but not DNMT3׳s gene expression was higher in FRDA cells. In conclusion, our data show that FRDA cells present altered expression of genes related to cell cycle, oxidative stress and iron homeostasis which may be implicated in the increased apoptotic levels. Also, the altered expression is in a certain degree normalized in the presence of idebenone and deferiprone.

Keywords: Apoptosis; DNA methylation; Frataxin; Friedreich׳s ataxia; Periodontal ligament cells; miRNAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Apoptosis / genetics
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Brain-Derived Neurotrophic Factor / biosynthesis
  • Caspase 3 / biosynthesis*
  • Cells, Cultured
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / biosynthesis
  • DNA Methylation
  • Decitabine
  • Deferiprone
  • Epigenesis, Genetic
  • Frataxin
  • Friedreich Ataxia / genetics*
  • Gene Expression Profiling
  • Humans
  • Iron Chelating Agents / pharmacology
  • Iron-Binding Proteins / biosynthesis*
  • MicroRNAs / biosynthesis*
  • Neuregulin-1 / biosynthesis
  • Oxidative Stress / genetics*
  • Periodontal Ligament / cytology
  • Pyridones / pharmacology
  • Superoxide Dismutase / genetics
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / pharmacology


  • Antioxidants
  • Brain-Derived Neurotrophic Factor
  • Iron Chelating Agents
  • Iron-Binding Proteins
  • MIRN132 microRNA, human
  • MIRN886 microRNA, human
  • MicroRNAs
  • NRG1 protein, human
  • Neuregulin-1
  • Pyridones
  • Ubiquinone
  • Deferiprone
  • BDNF protein, human
  • Decitabine
  • Superoxide Dismutase
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Caspase 3
  • idebenone
  • Azacitidine