title: 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, 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.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy.
authors.forename: Provvidenza Maria
authors.initials: PM
authors.lastname: Abruzzo
authors.forename: Marina
authors.initials: M
authors.lastname: Marini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bolotta
authors.forename: Gemma
authors.initials: G
authors.lastname: Malisardi
authors.forename: Stefano
authors.initials: S
authors.lastname: Manfredini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ghezzo
authors.forename: Antonella
authors.initials: A
authors.lastname: Pini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tasco
authors.forename: Rita
authors.initials: R
authors.lastname: Casadio
mesh_terms: D000595:Amino Acid Sequence; D013437:Carbon-Sulfur Lyases / Q000378:metabolism; D016022:Case-Control Studies; D018076:DNA, Complementary / Q000235:genetics; D019587:Dietary Supplements; D005621:Friedreich Ataxia / Q000188:drug therapy / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D033862:Iron-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D059368:RNA Isoforms / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024508:Tocotrienols / Q000494:pharmacology* / Q000627:therapeutic use; D000096923:Frataxin
chemical_list: D013437:Carbon-Sulfur Lyases; D018076:DNA, Complementary; D033862:Iron-Binding Proteins; D047495:PPAR gamma; D059368:RNA Isoforms; D024508:Tocotrienols; D000096923:Frataxin; C513492:NFS1 protein, human