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

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.

Selected missense mutations impair frataxin processing in Friedreich ataxia

“…In general, patients carrying G130V mutations have milder phenotypes in single case reports and small series. In contrast, individuals with mutations in W155R and R165C have much more severe phenotypes 9, 10, 11, 12…”

“…Many missense mutations in the C‐terminus end of FXN have been identified in FRDA, yet, few have been characterized in vivo or in situ. Some are proposed to disrupt mRNA expression (various splice site mutations such as c.165 + 1 G>A and c.384 −2 A>G),11, 12 translation initiation (c.1A>T, c.2T>C, c.2delT, c.3 g>T, c.3G>A), or protein folding (L106S) 9, 13, 14, 15. These should produce little to no functional protein, and their associated phenotype should be severe in conjunction with a long GAA repeat on the other FXN allele.…”

Co-precipitation of Phosphate and Iron Limits Mitochondrial Phosphate Availability in Saccharomyces cerevisiae Lacking the Yeast Frataxin Homologue (YFH1)

“…The effects of frataxin deficiency on iron metabolism in yeast have been studied extensively (reviewed in Ref. 4). But, as iron precipitates in the form of ferric phosphate in the mitochondria of ⌬yfh1 cells, the physiological consequences of iron accumulation/precipitation in these cells probably involve dysfunctions in both iron and phosphate metabolism.…”

The yeast metacaspase is implicated in oxidative stress response in frataxin‐deficient cells

“…Susceptibility to oxidative stress is not a primary defect of frataxin-deficiency but it is observed in all eukaryotic organisms studied and contributes largely to the cellular phenotypes [1,2,5]. Although it is recognized that the cellular antioxidant defense mechanisms are defective in frataxin-deficient cells, it is not clear which molecules among ROS accumulate and are responsible for the damage.…”

“…FA is a hereditary neurodegenerative disease caused by reduced expression of frataxin [3,4]. Frataxin deficiency in humans and model systems causes decreased biosynthesis of iron-sulfur cluster and heme cofactors, reduced respiratory capacity, disturbed iron homeostasis and hypersensitivity to oxidants [5]. Iron accumulation in the mitochondria, which can participate in the Fenton reaction and increase reactive oxygen species (ROS) production, is considered an important mechanism inducing oxidative stress in frataxin-deficient cells [1,2].…”