hdac inhibitors correct frataxin deficiency in a friedreich ataxia mouse modelhdac抑制剂正确缺frataxin friedreich共济失调小鼠模型.pdfVIP

HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model 1 2 2¤ 2 2 3 Myriam Rai , Elisabetta Soragni , Kai Jenssen , Ryan Burnett , David Herman , Giovanni Coppola , 3 2 1 Daniel H. Geschwind , Joel M. Gottesfeld , Massimo Pandolfo * ´ ˆ ´ 1 Laboratoire de Neurologie Experimentale, Hopital Erasme, Universite Libre de Bruxelles (ULB), Brussels, Belgium, 2 Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America, 3 Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America 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 GAA?TTC 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. Methodology/Principal Findings: By chromatin immunoprecipitation, we detecte