Frataxin mRNA isoforms in FRDA patients and normal subjects: effect of tocotrienol supplementation

Biomed Res Int. 2013;2013:276808. doi: 10.1155/2013/276808. Epub 2013 Sep 23.

Abstract

Friedreich's ataxia (FRDA) is caused by deficient expression of the mitochondrial protein frataxin involved in the formation of iron-sulphur complexes and by consequent oxidative stress. We analysed low-dose tocotrienol supplementation effects on the expression of the three splice variant isoforms (FXN-1, FXN-2, and FXN-3) in mononuclear blood cells of FRDA patients and healthy subjects. In FRDA patients, tocotrienol leads to a specific and significant increase of FXN-3 expression while not affecting FXN-1 and FXN-2 expression. Since no structural and functional details were available for FNX-2 and FXN-3, 3D models were built. FXN-1, the canonical isoform, was then docked on the human iron-sulphur complex, and functional interactions were computed; when FXN-1 was replaced by FXN-2 or FNX-3, we found that the interactions were maintained, thus suggesting a possible biological role for both isoforms in human cells. Finally, in order to evaluate whether tocotrienol enhancement of FXN-3 was mediated by an increase in peroxisome proliferator-activated receptor-γ (PPARG), PPARG expression was evaluated. At a low dose of tocotrienol, the increase of FXN-3 expression appeared to be independent of PPARG expression. Our data show that it is possible to modulate the mRNA expression of the minor frataxin isoforms and that they may have a functional role.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Carbon-Sulfur Lyases / metabolism
  • Case-Control Studies
  • DNA, Complementary / genetics
  • Dietary Supplements
  • Friedreich Ataxia / drug therapy
  • Friedreich Ataxia / genetics*
  • Gene Expression Regulation / drug effects
  • Humans
  • Iron-Binding Proteins / chemistry
  • Iron-Binding Proteins / genetics*
  • Iron-Binding Proteins / metabolism
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Protein Binding / drug effects
  • RNA Isoforms / genetics*
  • RNA Isoforms / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tocotrienols / pharmacology*
  • Tocotrienols / therapeutic use

Substances

  • DNA, Complementary
  • Iron-Binding Proteins
  • PPAR gamma
  • RNA Isoforms
  • Tocotrienols
  • frataxin
  • Carbon-Sulfur Lyases
  • NFS1 protein, human