Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities

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Abstract
Mitochondrial dysfunction and oxidative damage are at the origin of numerous neurodegenerative diseases like Friedreich ataxia and Alzheimer and Parkinson diseases. Friedreich ataxia (FRDA) is the most common hereditary ataxia, with one individual affected in 50,000. This disease is characterized by progressive degeneration of the central and peripheral nervous systems, cardiomyopathy, and increased incidence of diabetes mellitus. FRDA is caused by a dynamic mutation, a GAA trinucleotide repeat expansion, in the first intron of the FXN gene. Fewer than 5% of the patients are heterozygous and carry point mutations in the other allele. The molecular consequences of the GAA triplet expansion is transcription silencing and reduced expression of the encoded mitochondrial protein, frataxin. The precise cellular role of frataxin is not known; however, it is clear now that several mitochondrial functions are not performed correctly in patient cells. The affected functions include respiration, iron–sulfur cluster assembly, iron homeostasis, and maintenance of the redox status. This review highlights the molecular mechanisms that underlie the disease phenotypes and the different hypothesis about the function of frataxin. In addition, we present an overview of the most recent therapeutic approaches for this severe disease that actually has no efficient treatment. Antioxid. Redox Signal. 13, 651–690. Introduction and History Clinical Features and Pathogenesis of Friedreich Ataxia Epidemiology and clinical features Pathophysiology Mutations in the FXN Gene Cause FRDA Mapping and cloning of the FXN gene Structure and regulation of the FXN gene Developmental expression of the FXN gene Molecular mechanism of GAA triplet-repeat expansion Genotype–phenotype correlations Point mutations Frataxin Is a Unique Protein Phylogeny and structure of frataxin Frataxin maturation Cellular function of frataxin Frataxin Function in Cell Iron Use and Oxidative-Stress Defense Frataxin is critical for Fe-S cluster assembly Frataxin is involved in heme biosynthesis Iron homeostasis Iron-binding properties and oligomerization of frataxin Regulation of cellular antioxidant defenses Mitochondrial and nuclear genome integrity Frataxin Is Involved in Development, Cell Death, and Cancer Development in model organisms Susceptibility to cell death and neuron degeneration Cancer Therapeutic Approaches for Treatment of Friedreich Ataxia Evaluation of disease progression Antioxidants and oxidative phosphorylation Iron chelators Molecules that increase frataxin levels Conclusion