Abstract
Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes1,2. FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein3 of unknown function. Yeast knockout models as well as histological and biochemical data from heart biopsies or autopsies of FRDA patients have shown that frataxin defects cause a specific iron-sulfur protein deficiency and intramitochondrial iron accumulation4,5,6,7. We have recently shown that complete absence of frataxin in the mouse leads to early embryonic lethality8, demonstrating an important role for frataxin during mouse development. Through a conditional gene-targeting approach, we have generated in parallel a striated muscle frataxin-deficient line and a neuron/cardiac muscle frataxin-deficient line, which together reproduce important progressive pathophysiological and biochemical features of the human disease: cardiac hypertrophy without skeletal muscle involvement, large sensory neuron dysfunction without alteration of the small sensory and motor neurons, and deficient activities of complexes I–III of the respiratory chain and of the aconitases. Our models demonstrate time-dependent intramitochondrial iron accumulation in a frataxin-deficient mammal, which occurs after onset of the pathology and after inactivation of the Fe-S-dependent enzymes. These mutant mice represent the first mammalian models to evaluate treatment strategies for the human disease.
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Acknowledgements
We thank J.L. Mandel and members of his laboratory for discussions and comments; L. Reutenauer, N. Lagarde and P. Goetz-Reiner for technical support; N. Calizot for discussions and comments during the EMG analysis; and R. Kahn for the MCK-Cre transgenic animals. This work was supported by funds from the Human Frontier Science Program (HFSP), the European Community (contract QLRT-CT-1999-00584), the Association Française contre les Myopathies (AFM), the Association Française contre l'ataxie de Friedreich (AFAF), the Muscular Dystrophy Association of America (to M.K.), INSERM, CNRS and the Hôpital Universitaire de Strasbourg (HUS). M.C. is supported by the INSERM, H.P. by the HFSP.
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Puccio, H., Simon, D., Cossée, M. et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 27, 181–186 (2001). https://doi.org/10.1038/84818
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DOI: https://doi.org/10.1038/84818
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