Understanding the genetic and molecular pathogenesis of Friedreich's ataxia through animal and cellular models

Abstract

In 1996, a link was identified between Friedreich's ataxia (FRDA), the most common inherited ataxia in men, and alterations in the gene encoding frataxin (FXN). Initial studies revealed that the disease is caused by a unique, most frequently biallelic, expansion of the GAA sequence in intron 1 of FXN. Since the identification of this link, there has been tremendous progress in understanding frataxin function and the mechanism of FRDA pathology, as well as in developing diagnostics and therapeutic approaches for the disease. These advances were the subject of the 4th International Friedreich's Ataxia Conference held on 5th-7th May in the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. More than 200 scientists gathered from all over the world to present the results of research spanning all areas of investigation into FRDA (including clinical aspects, FRDA pathogenesis, genetics and epigenetics of the disease, development of new models of FRDA, and drug discovery). This review provides an update on the understanding of frataxin function, developments of animal and cellular models of the disease, and recent advances in trying to uncover potential molecules for therapy.

Fig. 1.

Frataxin is a mitochondrial protein with a key role in Fe-S cluster biogenesis. Over the past 10 years, frataxin has been proposed to be a multifunctional protein involved in providing iron to various mitochondrial proteins (represented by dashed arrows), including succinate dehydrogenase (SDH), mitochondrial aconitase (mACO) and ferrochelatase (FCH), as well as for Fe-S cluster biogenesis, which involves the cysteine desulfurase NFS1-ISD11 and the scaffold protein ISCU. SDH, mACO and FCH are Fe-S-containing proteins in mammals. Frataxin has also been proposed to form oligomeric structures that can store iron. In vitro, both monomeric and oligomeric forms of frataxin can provide iron for Fe-S cluster biogenesis. More recently, the existence of multiple frataxin protein partners, as well as the role of the oligomeric form of frataxin in vivo, were questioned (see text). Indeed, a tight and stable iron-independent complex between monomeric frataxin and the ISCU-NFS1-ISD11 complex was isolated (reprensented by solid arrows), and the ability of frataxin to form this complex was shown to correlate with the essential frataxin function in vivo (Tsai and Barondeau, 2010; Schmucker et al., 2011). Furthermore, these studies showed that, on frataxin binding, the cysteine desulfurase activity of the ISCU-NFS1-ISD11 complex is increased (red arrow), and Fe-S cluster biogenesis on ISCU is enhanced, suggesting that frataxin is a key modulator of de novo Fe-S cluster formation in vivo. PPIX, protoporphyrin IX.