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Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia.
FEBS Lett. 2006 Oct 02; 580(22):5399-405.FL

Abstract

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.

Authors+Show Affiliations

Department of Biochemistry, 2500 North State Street, The University of Mississippi Medical Center, Jackson, 39216-4505, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16989817

Citation

Grant, LaKechia, et al. "Rational Selection of Small Molecules That Increase Transcription Through the GAA Repeats Found in Friedreich's Ataxia." FEBS Letters, vol. 580, no. 22, 2006, pp. 5399-405.
Grant L, Sun J, Xu H, et al. Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia. FEBS Lett. 2006;580(22):5399-405.
Grant, L., Sun, J., Xu, H., Subramony, S. H., Chaires, J. B., & Hebert, M. D. (2006). Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia. FEBS Letters, 580(22), 5399-405.
Grant L, et al. Rational Selection of Small Molecules That Increase Transcription Through the GAA Repeats Found in Friedreich's Ataxia. FEBS Lett. 2006 Oct 2;580(22):5399-405. PubMed PMID: 16989817.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia. AU - Grant,LaKechia, AU - Sun,Jun, AU - Xu,Hongzhi, AU - Subramony,S H, AU - Chaires,Jonathan B, AU - Hebert,Michael D, Y1 - 2006/09/15/ PY - 2006/06/09/received PY - 2006/09/02/revised PY - 2006/09/05/accepted PY - 2006/9/23/pubmed PY - 2006/11/11/medline PY - 2006/9/23/entrez SP - 5399 EP - 405 JF - FEBS letters JO - FEBS Lett VL - 580 IS - 22 N2 - 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. SN - 0014-5793 UR - https://www.unboundmedicine.com/medline/citation/16989817/Rational_selection_of_small_molecules_that_increase_transcription_through_the_GAA_repeats_found_in_Friedreich's_ataxia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-5793(06)01084-2 DB - PRIME DP - Unbound Medicine ER -