title: TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich's Ataxia.
abstract: 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.
authors.affiliation: Department of Genetics, University of Valencia, Burjassot, Valencia, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Calap-Quintana
authors.affiliation: Department of Genetics, University of Valencia, Burjassot, Valencia, Spain; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Sirena
authors.initials: S
authors.lastname: Soriano
authors.affiliation: Department of Genetics, University of Valencia, Burjassot, Valencia, Spain.
authors.forename: José Vicente
authors.initials: JV
authors.lastname: Llorens
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.affiliation: Department of Genetics, University of Valencia, Burjassot, Valencia, Spain; CIBERSAM, INCLIVA, Valencia, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Moltó
authors.affiliation: Department of Genetics, University of Valencia, Burjassot, Valencia, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Martínez-Sebastián
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005621:Friedreich Ataxia / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000187:drug effects / Q000235:genetics; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D000255:Adenosine Triphosphate; D000447:Aldehydes; D000975:Antioxidants; D029721:Drosophila Proteins; D005978:Glutathione; D007166:Immunosuppressive Agents; D033862:Iron-Binding Proteins; D008315:Malondialdehyde; D012097:Repressor Proteins; D020123:Sirolimus; D013482:Superoxide Dismutase; D014157:Transcription Factors; D000096923:Frataxin; C570998:TORC1 protein complex, Drosophila; C116463:cnc protein, Drosophila; C027576:4-hydroxy-2-nonenal