TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia
TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia
Friedreich's ataxia (FRDA), the most common inherited ataxia in the Caucasian population, is a multisystemic disease caused by a significant decrease in the frataxin level. To identify genes capable of modifying the severity of the symptoms of frataxin depletion, we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. Pharmacologic inhibition of TORC1 signalling by rapamycin also restored this phenotype and increased the lifespan and ATP levels. Furthermore, rapamycin reduced the altered levels of malondialdehyde + 4-hydroxyalkenals and total glutathione of the model flies. The rapamycin-mediated protection against oxidative stress is due in part to an increase in the transcription of antioxidant genes mediated by cap-n-collar (Drosophila ortholog of Nrf2). Our results suggest that autophagy is indeed necessary for the protective effect of rapamycin in hyperoxia. Rapamycin increased the survival and aconitase activity of model flies subjected to high oxidative insult, and this improvement was abolished by the autophagy inhibitor 3-methyladenine. These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment.
- Baylor College of Medicine United States
- Uppsala University Sweden
- University of Valencia Spain
- BAYLOR COLLEGE OF MEDICINE
Male, Science, Longevity, Gene Expression, Motor Activity, Antioxidants, Animals, Genetically Modified, Adenosine Triphosphate, Iron-Binding Proteins, Malondialdehyde, Animals, Drosophila Proteins, Humans, Aconitate Hydratase, Aldehydes, Q, R, Glutathione, Disease Models, Animal, Oxidative Stress, Drosophila melanogaster, Friedreich Ataxia, Medicine, Immunosuppressive Agents, Research Article
Male, Science, Longevity, Gene Expression, Motor Activity, Antioxidants, Animals, Genetically Modified, Adenosine Triphosphate, Iron-Binding Proteins, Malondialdehyde, Animals, Drosophila Proteins, Humans, Aconitate Hydratase, Aldehydes, Q, R, Glutathione, Disease Models, Animal, Oxidative Stress, Drosophila melanogaster, Friedreich Ataxia, Medicine, Immunosuppressive Agents, Research Article
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