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

• Published in: BioMed research international Vol. 2013; no. 2013; pp. 1 - 9
• Main Authors: Casadio, Rita, Tasco, Gianluca, Ghezzo, Alessandro, Manfredini, Stefano, Malisardi, Gemma, Bolotta, Alessandra, Marini, Marina, Abruzzo, Provvidenza Maria, Pini, Antonella
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 01.01.2013; John Wiley & Sons, Inc
• Subjects: Alternative splicing; Amino Acid Sequence; Ataxia; Biomedical research; Carbon-Sulfur Lyases - metabolism; Case-Control Studies; Cell culture; Dietary Supplements; DNA, Complementary - genetics; Frataxin; Friedreich Ataxia - drug therapy; Friedreich Ataxia - genetics; Friedreich's ataxia; Gene expression; Gene Expression Regulation - drug effects; Genetic aspects; Humans; Identification and classification; Iron-Binding Proteins - chemistry; Iron-Binding Proteins - genetics; Iron-Binding Proteins - metabolism; Messenger RNA; Molecular Docking Simulation; Molecular Sequence Data; Oxidative stress; PPAR gamma - genetics; PPAR gamma - metabolism; Properties; Protein Binding - drug effects; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA Isoforms - genetics; RNA Isoforms - metabolism; Studies; Tocotrienols; Tocotrienols - pharmacology; Tocotrienols - therapeutic use
• ISSN: 2314-6133; 2314-6141; 2314-6141
• DOI: 10.1155/2013/276808

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.