Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac<br />disease, is caused by abnormally low levels of frataxin, an essential<br />mitochondrial protein. All Friedreich ataxia patients carry a GAATTC<br />repeat expansion in the first intron of the frataxin gene, either<br />in the homozygous state or in compound heterozygosity with other<br />loss-of-function mutations. The GAA expansion inhibits frataxin expression<br />through a heterochromatin-mediated repression mechanism. Histone<br />modifications that are characteristic of silenced genes in heterochromatic<br />regions occur at expanded alleles in cells from Friedreich ataxia<br />patients, including increased trimethylation of histone H3 at lysine<br />9 and hypoacetylation of histones H3 and H4.By chromatin immunoprecipitation,<br />we detected the same heterochromatin marks in homozygous mice carrying<br />a (GAA)(230) repeat in the first intron of the mouse frataxin gene<br />(KIKI mice). These animals have decreased frataxin levels and, by<br />microarray analysis, show significant gene expression changes in<br />several tissues. We treated KIKI mice with a novel histone deacetylase<br />inhibitor, compound 106, which substantially increases frataxin mRNA<br />levels in cells from Friedreich ataxia individuals. Treatment increased<br />histone H3 and H4 acetylation in chromatin near the GAA repeat and<br />restored wild-type frataxin levels in the nervous system and heart,<br />as determined by quantitative RT-PCR and semiquantitative western<br />blot analysis. No toxicity was observed. Furthermore, most of the<br />differentially expressed genes in KIKI mice reverted towards wild-type<br />levels.Lack of acute toxicity, normalization of frataxin levels and<br />of the transcription profile changes resulting from frataxin deficiency<br />provide strong support to a possible efficacy of this or related<br />compounds in reverting the pathological process in Friedreich ataxia,<br />a so far incurable neurodegenerative disease.
Rai, M., Soragni, E., Jenssen, K., Burnett, R., Herman, D., Coppola, G., … Pandolfo, M. (2008). HDAC inihibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS ONE, 3(4). https://doi.org/10.1371/journal.pone.0001958