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Friedreich's ataxia: the vicious circle hypothesis revisited

Aurélien Bayot12, Renata Santos3, Jean-Michel Camadro3 and Pierre Rustin12*

Author affiliations

1 Inserm, U676, Physiopathology and Therapy of Mitochondrial Diseases Laboratory, CHU - Hôpital Robert Debré, 48, boulevard Sérurier, F-75019 Paris, France

2 Faculté de médecine Denis Diderot, Université Paris-Diderot, IFR02, 16, rue Henri Huchard, F-75018, Paris, France

3 Institut Jacques Monod (UMR 7592 CNRS-Université Paris-Diderot), Mitochondria, Metals and Oxidative Stress Laboratory, Bâtiment Buffon - 15, rue Hélène Brion, F-75205 Paris, Cedex 13, France

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Citation and License

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

Published: 11 October 2011


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 FXN gene, which encodes the mitochondrial frataxin protein. Since FXN 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.