Abstract | BACKGROUND: 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.
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Authors | Myriam Rai, Elisabetta Soragni, Kai Jenssen, Ryan Burnett, David Herman, Giovanni Coppola, Daniel H Geschwind, Joel M Gottesfeld, Massimo Pandolfo |
Journal | PloS one
(PLoS One)
Vol. 3
Issue 4
Pg. e1958
(Apr 09 2008)
ISSN: 1932-6203 [Electronic] United States |
PMID | 18463734
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Chromatin
- Enzyme Inhibitors
- Histone Deacetylase Inhibitors
- Histones
- Iron-Binding Proteins
- RNA, Messenger
- frataxin
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Topics |
- Acetylation
(drug effects)
- Animals
- Cerebellum
(drug effects, metabolism)
- Chromatin
(metabolism)
- Disease Models, Animal
- Enzyme Inhibitors
(pharmacology, therapeutic use)
- Epigenesis, Genetic
(drug effects)
- Friedreich Ataxia
(drug therapy)
- Gene Expression Profiling
- Histone Deacetylase Inhibitors
- Histones
(metabolism)
- Introns
(genetics)
- Iron-Binding Proteins
(genetics, metabolism)
- Mice
- Myocardium
(metabolism)
- Protein Processing, Post-Translational
(drug effects)
- RNA, Messenger
(genetics, metabolism)
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