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Published on: July 11, 2019
A Yeast/Drosophila Screen to Identify New Compounds Overcoming Frataxin Deficiency
Alexandra Seguin1, Véronique Monnier2, Amandine Palandri2
1"Mitochondries, Métaux et Stress Oxydant", Institut Jacques Monod, UMR7592 CNRS-Université Paris Diderot, Sorbonne Paris Cité, 15 rue Hélène Brion, 75205 Paris Cedex 13, France.
Abstract:
Friedreich's ataxia (FA) is a rare neurodegenerative disease which is very debilitating for the patients who progressively lose their autonomy. The lack of efficient therapeutic treatment of the disease strongly argues for urgent need to search for new active compounds that may stop the progression of the disease or prevent the appearance of the symptoms when the genetic defect is diagnosed early enough. In the present study, we used a yeast strain with a deletion of the frataxin homologue gene as a model of FA cells in a primary screen of two chemical libraries, a fraction of the French National Chemical Library (5500 compounds) and the Prestwick collection (880 compounds). We ran a secondary screen on Drosophila melanogaster flies expressing reduced levels of frataxin during larval development. Half of the compounds selected in yeast appeared to be active in flies in this developmental paradigm, and one of the two compounds with highest activities in this assay partially rescued the heart dilatation phenotype resulting from heart specific depletion of frataxin. The unique complementarity of these two frataxin-deficient models, unicellular and multicellular, appears to be very efficient to select new compounds with improved selectivity, bringing significant perspectives towards improvements in FA therapy.
Insights
Researchers screened chemical libraries using yeast and fly models to find treatments for Friedreich
Area of Science:
- Neurodegenerative disease research
- Drug discovery and development
- Genetics and molecular biology
Background:
- Friedreich's ataxia (FA) is a rare, debilitating neurodegenerative disease.
- Current therapeutic options for FA are limited, necessitating the search for new treatments.
- Early diagnosis and intervention are crucial for managing FA symptoms and progression.
Purpose of the Study:
- To identify novel compounds for Friedreich's ataxia (FA) therapy.
- To evaluate the efficacy of compounds using complementary yeast and Drosophila melanogaster models.
- To explore potential treatments that could halt disease progression or prevent symptom onset.
Main Methods:
- Primary screening of 5500 compounds from the French National Chemical Library and 880 from the Prestwick collection using a yeast model deficient in frataxin.
- Secondary screening of selected compounds in Drosophila melanogaster larvae with reduced frataxin levels.
- Assessment of compound activity through developmental paradigms and rescue of heart dilatation phenotype.
Main Results:
- Approximately 50% of compounds active in the yeast model also showed activity in the Drosophila melanogaster model.
- One compound demonstrated significant activity, partially rescuing the heart dilatation phenotype in flies.
- The combined yeast and fly models proved effective in selecting compounds with improved selectivity.
Conclusions:
- The study successfully identified potential therapeutic compounds for Friedreich's ataxia (FA).
- The dual-model approach (yeast and fly) offers a robust strategy for drug discovery in FA.
- These findings provide significant promise for the development of improved FA therapies.
