title: HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model.
abstract: BACKGROUND
  Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAATTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4.
  
  
  RESULTS
  By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)(230) repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels.
  
  
  CONCLUSIONS
  Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease.
authors.affiliation: Laboratoire de Neurologie Expérimentale, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Rai
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soragni
authors.forename: Kai
authors.initials: K
authors.lastname: Jenssen
authors.forename: Ryan
authors.initials: R
authors.lastname: Burnett
authors.forename: David
authors.initials: D
authors.lastname: Herman
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005621:Friedreich Ataxia / Q000188:drug therapy*; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D007438:Introns / Q000235:genetics; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000096923:Frataxin
chemical_list: D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D033862:Iron-Binding Proteins; D012333:RNA, Messenger; D000096923:Frataxin