Friedreich ataxia originates from a decrease in mitochondrial frataxin, which causes the death of a subset of neurons. The biochemical hallmarks of the disease include low activity of the iron sulfur cluster-containing proteins (ISP) and impairment of antioxidant defense mechanisms that may play a major role in disease progression.

Methodology/Principal Findings

We thus investigated signaling pathways involved in antioxidant defense mechanisms. We showed that cultured fibroblasts from patients with Friedreich ataxia exhibited hypersensitivity to oxidative insults because of an impairment in the Nrf2 signaling pathway, which led to faulty induction of antioxidant enzymes. This impairment originated from previously reported actin remodeling by hydrogen peroxide.


Thus, the defective machinery for ISP synthesis by causing mitochondrial iron dysmetabolism increases hydrogen peroxide production that accounts for the increased susceptibility to oxidative stress.

Authors: Vincent Paupe1,2, Emmanuel P. Dassa1,2, Sergio Goncalves1,2, Françoise Auchère3, Maria Lönn4, Arne Holmgren4, Pierre Rustin1,2*

1 Inserm, U676, Hôpital Robert Debré, Bât. Ecran, Paris, France, 2 Faculté de médecine Denis Diderot, IFR02, Université Paris 7, Laboratoire d'Ingénierie des Protéines et Contrôle Métabolique, Paris, France, 3 Département de Biologie des Génomes, Institut Jacques Monod (UMR 7592 CNRS - Universités Paris 6 & 7), Paris, France, 4 Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm, Sweden

Citation: Paupe V, Dassa EP, Goncalves S, Auchère F, Lönn M, et al. (2009) Impaired Nuclear Nrf2 Translocation Undermines the Oxidative Stress Response in Friedreich Ataxia. PLoS ONE 4(1): e4253. doi:10.1371/journal.pone.0004253

Editor: Antoni L. Andreu, Hospital Vall d'Hebron, Spain

Received: October 3, 2008; Accepted: December 15, 2008; Published: January 22, 2009

Copyright: © 2009 Paupe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by Friedreich ataxia patient organizations in France (AFAF and REVAmoto), Switzerland (ACHAF), and the US (FARA). EPD and PR were supported by the European Community sixth Framework Program for Research, contract number LSHM-CT-2004-503116; EPD and PR by the Leducq foundation; SG, V, and PR by the ANR MRAR Friedreich project; and PR by the AFM (Association Française contre les Myopathies) and AMMi (Association contre les Maladies Mitochondriales). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

This abstract has been kindly provided by Juan Carlos Baiges

Source: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004253

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Research projects currently being financed by BabelFAmily

Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:

1) Gene Therapy for Friedreich's Ataxia research project:


The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.

2) Frataxin delivery research project:

The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.

The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.



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