Catalase overexpression rescues Friedreich’s Ataxia mouse models from oxidative stress and mitochondrial iron-loading

Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disorder characterized by gait disturbance and speech problems. Disease pathology is characterized by progressive damage and loss of nerve tissue particular to the peripheral nerve system. FRDA is caused by the relative deficiency of a mitochondrial protein frataxin resulting from an expanded intronic GAA triplet repeat. While the precise role of frataxin has been the subject of controversy for the past decade, it is well accepted that FRDA pathology is related to mitochondrial dysfunction. Yeast and Drosophila models of FRDA exhibit signs of oxidative damage which has led us to the hypothesis that catalase over expression will rescue frataxin deficient peripheral neuronal cells and that H2O2 plays a critical role in FRDA pathogenesis. Furthermore, by eliminating the cell content of H2O2 we can alleviate some of the symptoms of FRDA. To test our hypothesis, we aim to i) generate a conditional knockout mice expressing frataxin deficiency in the nervous system as our model for studying hydrogen peroxide toxicity, ii) manipulate cell content of H2O2 by modulating the amount of catalase and iii) investigate the regulation of mitochondrial iron loading proteins in the same model system.