title: 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 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.
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia and Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Marguerite V
authors.initials: MV
authors.lastname: Evans-Galea
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
authors.forename: Charles A
authors.initials: CA
authors.lastname: Galea
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
mesh_terms: D000483:Alleles; D005621:Friedreich Ataxia / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D000096923:Frataxin