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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Salin, Bénédicte Ezkurdia, Nahia Le Cann, Marie Kabala, Anna Steinmetz, Lars M. Aiyar, Raeka S. Di Rago, Jean-paul Kucharczyk, Roza Couplan, Elodie Soubigou, Flavie Blondel, Marc Gagneur, Julien St Onge, Robert P. |
| Description | Author Affiliation: Couplan E ( INSERM U613); |
| Abstract | Due to the lack of relevant animal models, development of effective treatments for human mitochondrial diseases has been limited. Here we establish a rapid, yeast-based assay to screen for drugs active against human inherited mitochondrial diseases affecting ATP synthase, in particular NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. This method is based on the conservation of mitochondrial function from yeast to human, on the unique ability of yeast to survive without production of ATP by oxidative phosphorylation, and on the amenability of the yeast mitochondrial genome to site-directed mutagenesis. Our method identifies chlorhexidine by screening a chemical library and oleate through a candidate approach. We show that these molecules rescue a number of phenotypes resulting from mutations affecting ATP synthase in yeast. These compounds are also active on human cybrid cells derived from NARP patients. These results validate our method as an effective high-throughput screening approach to identify drugs active in the treatment of human ATP synthase disorders and suggest that this type of method could be applied to other mitochondrial diseases. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 29 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Chlorhexidine Pharmacology Drug Discovery Drug Evaluation, Preclinical Mitochondrial Myopathies Drug Therapy Mitochondrial Proton-Translocating ATPases Genetics Oleic Acid Retinitis Pigmentosa Cell Line Therapeutic Use Gene Expression Profiling Mutagenesis, Site-Directed Mutation Saccharomycetales Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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