Friedreich's ataxia: the vicious circle hypothesis revisited

• Main Authors: Camadro Jean-Michel, Santos Renata, Bayot Aurélien, Rustin Pierre
• Format: Article
• Language: English
• Published: BMC 2011-10-01
• Series: BMC Medicine
• Online Access: http://www.biomedcentral.com/1741-7015/9/112

<p>Abstract</p> <p>Friedreich's ataxia, the most frequent progressive autosomal recessive disorder involving the central and peripheral nervous systems, is mostly associated with unstable expansion of GAA trinucleotide repeats in the first intron of the <it>FXN </it>gene, which encodes the mitochondrial frataxin protein. Since <it>FXN </it>was shown to be involved in Friedreich's ataxia in the late 1990s, the consequence of frataxin loss of function has generated vigorous debate. Very early on we suggested a unifying hypothesis according to which frataxin deficiency leads to a vicious circle of faulty iron handling, impaired iron-sulphur cluster synthesis and increased oxygen radical production. However, data from cell and animal models now indicate that iron accumulation is an inconsistent and late event and that frataxin deficiency does not always impair the activity of iron-sulphur cluster-containing proteins. In contrast, frataxin deficiency appears to be consistently associated with increased sensitivity to reactive oxygen species as opposed to increased oxygen radical production. By compiling the findings of fundamental research and clinical observations we defend here the opinion that the very first consequence of frataxin depletion is indeed an abnormal oxidative status which initiates the pathogenic mechanism underlying Friedreich's ataxia.</p>