Friedreich's ataxia: the vicious circle hypothesis revisited

BMC Medicine

Opinion

Aurélien Bayot¹  Pierre Rustin¹  Renata Santos²  Jean-Michel Camadro² 

[1] Inserm, U676, Physiopathology and Therapy of Mitochondrial Diseases Laboratory, CHU - Hôpital Robert Debré, 48, boulevard Sérurier, F-75019, Paris, France;Faculté de médecine Denis Diderot, Université Paris-Diderot, IFR02, 16, rue Henri Huchard, F-75018, Paris, France;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;

关键词: Idebenone;    Oxidative Insult;    International Cooperative Ataxia Rate Scale;    Sideroblastic Anaemia;    Mitochondrial Iron;   

DOI  :  10.1186/1741-7015-9-112

 received in 2011-05-17, accepted in 2011-10-11,  发布年份 2011

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Bayot et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.