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Series GSE10745 Query DataSets for GSE10745
Status Public on Mar 08, 2008
Title HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model
Organism Mus musculus
Experiment type Expression profiling by array
Summary 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 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/Significance: 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.
Keywords: drug response
 
Overall design Two mouse strains (KIKI and KO) were treated with compound 106 or control. Three tissues (Brain, Cerebellum, Heart) were examined in quadruplicate, for a total 48 arrays.
 
Contributor(s) Rai M, Soragni E, Jenssen K, Burnett R, Herman D, Coppola G, Geschwind DH, Gottesfeld JM, Pandolfo M
Citation(s) 18463734
Submission date Mar 06, 2008
Last update date Jan 18, 2013
Contact name Giovanni Coppola
E-mail(s) gcoppola@ucla.edu
Phone 310-794-4172
Organization name UCLA
Department Psychiatry and Neurology
Lab Neurogenetics
Street address 1524 Gonda, 695 Charles Young Drive South
City Los Angeles
State/province CA
ZIP/Postal code 90095
Country USA
 
Platforms (1)
GPL6103 Illumina mouseRef-8 v1.1 expression beadchip
Samples (48)
GSM271006 KIKI_c_B_1
GSM271007 KIKI_c_B_2
GSM271008 KIKI_c_B_3
Relations
BioProject PRJNA107523

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE10745_Microarray_raw_data.txt 41.2 Mb (ftp)(http) TXT
GSE10745_RAW.tar 3.4 Mb (http)(custom) TAR
Processed data included within Sample table

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