Friedreich ataxia (FRDA) is a devastating
neurodegenerative disease caused by mutations in the
frataxin gene (FXN).
Frataxin is an essential
protein which localizes to the mitochondria and is required for the synthesis of
iron-
sulfur clusters and
heme. Most individuals with FRDA are homozygous for trinucleotide GAA.TTC repeat expansions in intron 1 of FXN. The instability of these GAA.TTC repeats, the formation of non-
B DNA GAA.TTC structures, and accompanying epigenetic changes lead to reduced FXN transcript and
frataxin protein. This 'loss of
frataxin' is considered the main driver of disease pathology with mitochondria-rich tissues such as the heart and the brain most affected. While our understanding of FRDA etiology has advanced in recent years, exactly how reduced
frataxin leads to disease remains largely unknown. Most therapeutic strategies aim to increase
frataxin, yet there are other underlying aspects of the molecular pathology that could impact
disease progression and severity. These include
RNA toxicity due to antisense RNAs, dysregulated splicing and
microRNAs, and repeat-associated
protein toxicity via RAN translation. Here we review the diverse array of molecular events that have been shown to influence clinical outcome in FRDA. We also examine additional pathogenic factors from other trinucleotide repeat diseases which could be potentially important in FRDA.