Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits

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 diabetes. FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein 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 accumulation. We have recently shown that complete absence of frataxin in the mouse leads to early embryonic lethality, 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.

The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation

“…To this end, we examined the Fe metabolism of MCK mutants and the potential of Fe chelation to prevent cardiomyopathy. This model was chosen as it closely reflects the alterations in the heart of FA patients, including MIT Fe loading (5). The Fe accumulation is observed only after 7 weeks of age, with no detectable deposits being found earlier (5).…”

“…Many studies infer a role for Fxn in MIT iron (Fe) metabolism, particularly iron-sulfur cluster (ISC) biosynthesis (2,3). Deletion of the yeast Fxn homolog 1 gene or loss of Fxn in FA patients or Fxn knockout (mutant) mice promotes MIT Fe accumulation, hypersensitivity to oxidants, and the loss of MIT DNA and ISC-containing enzymes (2)(3)(4)(5). Increased cardiac Fe deposition and perturbations in heme biosynthesis and ATP production suggest that FA pathogenesis is linked to MIT Fe overload (6).…”

“…To test the potential of Fe chelation therapy for FA treatment, we have used muscle creatine kinase (MCK) conditional Fxn knockout mice lacking Fxn in cardiomyocytes (5). This model exhibits classical phenotypic traits of the cardiomyopathy in FA, including marked cardiac MIT Fe accumulation and deficiency in ISC enzymes (5).…”

Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols

“…In patients and various models of Friedreich's ataxia, Fe-S cluster biogenesis and iron metabolism are impaired 2,3 . Initial studies on eukaryotic and prokaryotic FXNs suggested roles in iron storage 4 , delivery 5 and detoxification 6 , but the physiological relevance of these functions has been questioned [7][8][9][10] .…”

Modèles animaux des maladies neuro-dégénératives

“…Plusieurs souris invalidées pour le gène de la frataxine ont été produites par une technique de ciblage génique conditionnel. Elles développent les principales lésions observées au cours de la maladie humaine : atteinte du cervelet et du ganglion spinal [45], cardiomyopathie [46] et diabète [47]. Elles ont permis de tester de nouvelles molé-cules thérapeutiques.…”