4.5 Article

Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia

期刊

FEBS LETTERS
卷 580, 期 22, 页码 5399-5405

出版社

WILEY
DOI: 10.1016/j.febslet.2006.09.006

关键词

neurodegenerative; trinucleotide repeat; competition dialysis; GFP

资金

  1. NCI NIH HHS [R01 CA035635] Funding Source: Medline

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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 I 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. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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