Friedreich ataxia: The vicious circle hypothesis revisited

BMC Medicine 2011, 9:112doi:10.1186/1741-7015-9-112, Published: 11 October 2011

Aurelien Bayot, Renata Santos, Jean-Michel Camadro and Pierre Rustin

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Abstract (provisional)
Friedreich ataxia, the most frequent progressive autosomal recessive disorder involving the central and peripheral nervous system, is mostly associated with an unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene which encodes the mitochondrial frataxin protein. Since FXN was shown to be involved in Friedreich ataxia in the late 1990s, the consequence of frataxin loss of function has been generating 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-sulfur 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-sulfur cluster-containing proteins. In contrast, frataxin deficiency appears consistently associated with increased sensitivity to reactive oxygen species, as opposed to increased oxygen radical production. Compiling findings from fundamental researches to 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 ataxia.

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