Document Detail

Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia.
MedLine Citation:
PMID:  16989817     Owner:  NLM     Status:  MEDLINE    
Friedreich's ataxia (FRDA) is an autosomal recessive trinucleotide repeat disease with no effective therapy. Expanded GAA repeats in the first intron of the FRDA gene are thought to form unusual non-B DNA conformations that decrease transcription and subsequently reduce levels of the encoded protein, frataxin. Frataxin plays a crucial role in iron metabolism and detoxification. To discover small molecules that increase transcription through the GAA repeat region in FRDA, we have made stable cell lines containing a portion of expanded intron 1 fused to a GFP reporter. Small molecules identified using the competition dialysis method were found to increase FRDA-intron 1-reporter gene expression. One of these compounds, pentamidine, increases frataxin levels in patient cells. Thus our approach can be used to detect small molecules of potential therapeutic value in FRDA.
LaKechia Grant; Jun Sun; Hongzhi Xu; S H Subramony; Jonathan B Chaires; Michael D Hebert
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-09-15
Journal Detail:
Title:  FEBS letters     Volume:  580     ISSN:  0014-5793     ISO Abbreviation:  FEBS Lett.     Publication Date:  2006 Oct 
Date Detail:
Created Date:  2006-09-26     Completed Date:  2006-11-09     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  0155157     Medline TA:  FEBS Lett     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  5399-405     Citation Subset:  IM    
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MeSH Terms
Antifungal Agents / pharmacology*
Cells, Cultured
Drug Design
Drug Evaluation, Preclinical
Friedreich Ataxia / drug therapy*,  genetics,  metabolism*,  pathology
Genes, Reporter / drug effects,  genetics
Iron-Binding Proteins / biosynthesis*,  genetics
Lymphocytes / metabolism,  pathology
Nucleic Acid Conformation / drug effects
Pentamidine / analogs & derivatives,  pharmacology*
Transcription, Genetic / drug effects*,  genetics
Trinucleotide Repeat Expansion / drug effects,  genetics
Grant Support
Reg. No./Substance:
0/Antifungal Agents; 0/Iron-Binding Proteins; 0/frataxin; 673LC5J4LQ/Pentamidine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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