Beyond loss of frataxin: The complex molecular pathology of friedreich ataxia

Abstract

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 ..