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Tytuł pozycji:

HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model.

Tytuł :
HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model.
Index Terms :
Sciences bio-médicales et agricoles
Acetylation -- drug effects
Animals
Cerebellum -- drug effects
Cerebellum -- metabolism
Chromatin -- metabolism
Disease Models, Animal
Enzyme Inhibitors -- pharmacology
Enzyme Inhibitors -- therapeutic use
Epigenesis, Genetic -- drug effects
Friedreich Ataxia -- drug therapy
Gene Expression Profiling
Histone Deacetylase Inhibitors
Histones -- metabolism
Introns -- genetics
Iron-Binding Proteins -- genetics
Iron-Binding Proteins -- metabolism
Mice
Myocardium -- metabolism
Protein Processing, Post-Translational -- drug effects
RNA, Messenger -- genetics
RNA, Messenger -- metabolism
info:eu-repo/semantics/article
info:ulb-repo/semantics/articlePeerReview
info:ulb-repo/semantics/openurl/article
Wydawca :
2008
Dodane szczegóły :
Rai, Myriam
Soragni, Elisabetta
Jenssen, Kai
Burnett, Ryan
Herman, David
Coppola, Giovanni
Geschwind, Daniel H
Gottesfeld, Joel M
Pandolfo, Massimo
Typ dokumentu :
Zasób elektroniczny
URL :
http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/51452
http://worldcat.org/search?q=on:EQY+http://difusion-oai.ulb.ac.be/oai/request+DCG_ENTIRE_REPOSITORY+CNTCOLL
Dostępność :
Open access content. Open access content
1 full-text file(s): info:eu-repo/semantics/openAccess
Pozostałe numery :
EQY oai:dipot.ulb.ac.be:2013/51452
uri/info:doi/10.1371/journal.pone.0001958
uri/info:pmid/18463734
uri/info:scp/44349114629
uri/info:pmcid/PMC2373517
https://dipot.ulb.ac.be/dspace/bitstream/2013/51452/4/doi_26541.pdf
764592850
Źródło wspomagające :
UNIV LIBR DE BRUXELLES
From OAIster®, provided by the OCLC Cooperative.
Numer akcesji :
edsoai.ocn764592850
Zasób elektroniczny
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. 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.
Journal Article
Research Support, N.I.H. Extramural
Research Support, Non-U.S. Gov't
info:eu-repo/semantics/published

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