Pathogenic Mechanisms in Friedreich Ataxia

Altered iron metabolism, free-radical damage, and mitochondrial dysfunction all occur in FA patients, suggesting that information derived from investigations on frataxin function and from the yeast and animal models is relevant for the pathogenesis of the human disease. Oxidative stress is revealed by increased plasma levels of malondialdheyde, a lipid peroxidation product (Emond et al. 2000), increased urinary 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage (Schulz et al. 2000), decreased plasmafree glutathione (Piemonte et al. 2001) and elevated plasma glutathione S-transferase activity (Tozzi et al. 2002). Increased free-radical production could be directly demonstrated in cultured cells engineered to produce reduced levels of frataxin (Santos et al. 2001). In addition, H2O2 induces apop-tosis in patients' fibroblasts at lower doses than in control fibroblasts (Wong et al. 1999), suggesting that even nonaffected cells are at risk for oxidative stress as a consequence of the primary genetic defect. FA fibroblasts also show abnormal antioxidant responses, in particular a blunted increase in mitochondrial superoxide dismutase triggered by iron and by oxidants in control cells (Jiralerspong et al. 2001). Mitochondrial dysfunction has been proven to occur in vivo in FA patients. Phosphorus magnetic resonance spec-troscopy analysis of skeletal muscle and heart shows a reduced rate of ATP synthesis (Lodi et al. 1999). Finally and most importantly, the same multiple ISC-containing enzyme dysfunctions found in Ayfh1 yeast and in mouse models are also found in affected tissues from FA patients (Rotig et al. 1997).

Activation of stress pathways, triggered by mitochondrial dysfunction, occurs in FA and is likely to play an important role in cell atrophy and death. Studies on cultured PC12 cells, rat pheochromocytoma cells that can be differentiated into neurons by adding nerve growth factor, showed in particular an increased expression and activity of the MKK4-JNK kinase pathway, which may be at first a protective response but eventually triggers apoptosis. Different vulnerable cell types may activate different pathways, as suggested by the observation of the specific occurrence of autophagic vacuoles only in primary sensory neurons in the inducible conditional knockout mouse model (Simon et al. 2004).

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