Friedreich's Ataxia: from the (GAA)n repeat mediated silencing to new promising molecules for therapy.
Friedreich's ataxia (FRDA) is a neurodegenerative disease due to a pathological expansion of a GAA triplet repeat in the first intron of the FXN gene encoding for the mitochondrial protein frataxin. The expansion is responsible for most cases of FRDA through the formation of a nonusual B-DNA structure and heterochromatin conformation that determine a direct transcriptional silencing and the subsequent reduction in frataxin expression. Among other functions, frataxin is an iron chaperone central for the assembly of iron-sulfur clusters in mitochondria; its reduction is associated with iron accumulation in mitochondria, increased cellular sensitivity to oxidative stress and cell damage. There is, nowadays, no effective therapy for FRDA and current therapeutic strategies mainly act to slow down the consequences of frataxin deficiency. Therefore, drugs that are able to increase the amount of frataxin are excellent candidates for a rational approach to FRDA therapy. Recently, several drugs have been assessed for their ability to increase the amount of cellular frataxin, including human recombinant erythropoietin, histone deacetylase inhibitors, and the PPAR-gamma agonists.
Marmolino
Daniele
D
Laboratoire de Neurologie Expérimentale, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, daniele.marmolino@ulb.ac.be
Acquaviva
Fabio
F
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D005617:Chlorofluorocarbons, Methane / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005621:Friedreich Ataxia / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy*; D020868:Gene Silencing / Q000502:physiology; D006570:Heterochromatin / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D033862:Iron-Binding Proteins / Q000235:genetics*; D008954:Models, Biological; D047495:PPAR gamma / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D018911:Trinucleotide Repeats / Q000235:genetics*; D000096923:Frataxin
D000975:Antioxidants; D005617:Chlorofluorocarbons, Methane; D004791:Enzyme Inhibitors; D006570:Heterochromatin; D006655:Histone Deacetylases; D006657:Histones; D007501:Iron; D007502:Iron Chelating Agents; D033862:Iron-Binding Proteins; D047495:PPAR gamma; D014157:Transcription Factors; D000096923:Frataxin; C005848:trichlorofluoromethane