Human Molecular Genetics Advance Access published online on March 17, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh114
© 2004 by Oxford University Press
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1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch cedex, CU de Strasbourg, France
* To whom correspondence should be addressed. E-mail: hpuccio{at}igbmc.u-strasbg.fr.
Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associated with cardiomyopathy, is caused by severely reduced frataxin, a mitochondrial protein involved in Fe-S cluster assembly. We have recently generated mouse models that reproduce important progressive pathological and biochemical features of the human disease. Our frataxin-deficient mouse models initially demonstrate time-dependent intramitochondrial iron saccumulation, which occurs after onset of the pathology and after inactivation of the Fe-S dependent enzymes. Here, we report a more detailed pathophysiological characterisation of our mouse model with isolated cardiac disease by echocardiographic, biochemical and histological studies and its use for placebo controlled therapeutic trial with Idebenone. The Fe-S enzyme deficiency occurs at 4 weeks of age, prior to cardiac dilatation and concomitant development of left ventricular hypertrophy, while the mitochondrial iron accumulation occurs at a terminal stage. From 7 weeks onward, Fe-S enzyme activities are strongly decreased and are associated with lower levels of oxidative stress markers, as a consequence of reduced respiratory chain activity. Furthermore, we demonstrate that the antioxidant Idebenone delays the cardiac disease onset, progression and death of frataxin deficient animals by one week, but does not correct the Fe-S enzyme deficiency. Our results support the view that frataxin is a necessary albeit non-essential component of the Fe-S cluster biogenesis, and indicate that Idebenone acts downstream of the primary Fe-S enzyme deficit. Furthermore, our results demonstrate that Idebenone is cardioprotective even in the context of a complete lack of frataxin, which further supports its utilisation for the treatment of FRDA.
Article
Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich Ataxia
2 Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, INSERM E333, Faculté de Médecine, 67085 Strasbourg cedex, France
3 Unité de Recherche sur les Handicaps Génétiques de l'Enfant, INSERM U393, Hôpital Necker-Enfants Malades, 75015 Paris, France
4 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/Université Louis Pasteur, 1 rue Laurent Fries BP 10142, 67404 Illkirch cedex, CU de Strasbourg, France
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