Friedreich ataxia: molecular mechanisms, redox considerations, and therapeutic opportunities.
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.
Santos
Renata
R
Mitochondria, Metals and Oxidative Stress Laboratory, Institut Jacques Monod (UMR 7592 CNRS-University Paris-Diderot), Paris, France.
Lefevre
Sophie
S
Sliwa
Dominika
D
Seguin
Alexandra
A
Camadro
Jean-Michel
JM
Lesuisse
Emmanuel
E
D000818:Animals; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D033862:Iron-Binding Proteins / Q000737:chemistry / Q000502:physiology; D008954:Models, Biological; D010084:Oxidation-Reduction; D000096923:Frataxin
D033862:Iron-Binding Proteins; D000096923:Frataxin