Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model

Hum Mol Genet. 2012 Jul 1;21(13):2855-61. doi: 10.1093/hmg/dds110. Epub 2012 Mar 23.

Abstract

Friedreich's ataxia (FRDA) is the most common hereditary ataxia, affecting ∼3 in 100 000 individuals in Caucasian populations. It is caused by intronic GAA repeat expansions that hinder the expression of the FXN gene, resulting in defective levels of the mitochondrial protein frataxin. Sensory neurons in dorsal root ganglia (DRG) are particularly damaged by frataxin deficiency. There is no specific therapy for FRDA. Here, we show that frataxin levels can be upregulated by interferon gamma (IFNγ) in a variety of cell types, including primary cells derived from FRDA patients. IFNγ appears to act largely through a transcriptional mechanism on the FXN gene. Importantly, in vivo treatment with IFNγ increases frataxin expression in DRG neurons, prevents their pathological changes and ameliorates the sensorimotor performance in FRDA mice. These results disclose new roles for IFNγ in cellular metabolism and have direct implications for the treatment of FRDA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Friedreich Ataxia / drug therapy
  • Friedreich Ataxia / genetics*
  • Friedreich Ataxia / metabolism*
  • Friedreich Ataxia / pathology
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • HeLa Cells
  • Humans
  • Interferon-gamma / pharmacology*
  • Interferon-gamma / physiology*
  • Interferon-gamma / therapeutic use
  • Iron-Binding Proteins / biosynthesis*
  • Iron-Binding Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Transcription, Genetic
  • Transcriptional Activation

Substances

  • Iron-Binding Proteins
  • frataxin
  • Interferon-gamma