Frataxin mRNA Isoforms in FRDA Patients and Normal Subjects: Effect of Tocotrienol Supplementation

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, andFXN-3) in mononuclear blood cells of FRDA patients and healthy subjects. In FRDA patients, tocotrienol leads to a specific and significant increase ofFXN-3expression while not affectingFXN-1andFXN-2expression. 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 ofFXN-3was mediated by an increase in peroxisome proliferator-activated receptor-γ(PPARG),PPARGexpression was evaluated. At a low dose of tocotrienol, the increase ofFXN-3expression appeared to be independent ofPPARGexpression. 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.