RESUMEN
Friedreich's ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Unión al ADN/genética , Drosophila/genética , Ataxia de Friedreich/metabolismo , Hierro/metabolismo , Factores de Transcripción/genética , Aluminio/metabolismo , Animales , Antioxidantes/metabolismo , Cobre/metabolismo , Modelos Animales de Enfermedad , Ataxia de Friedreich/genética , Homeostasis , Humanos , Proteínas de Unión a Hierro/genética , Manganeso/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Zinc/metabolismo , Frataxina , Factor de Transcripción MTF-1RESUMEN
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.
Asunto(s)
Antioxidantes/metabolismo , Proteínas de Drosophila/antagonistas & inhibidores , Drosophila melanogaster/metabolismo , Ataxia de Friedreich/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sirolimus/farmacología , Factores de Transcripción/antagonistas & inhibidores , Aconitato Hidratasa/metabolismo , Adenosina Trifosfato/metabolismo , Aldehídos/metabolismo , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Ataxia de Friedreich/genética , Expresión Génica , Glutatión/metabolismo , Humanos , Inmunosupresores/farmacología , Proteínas de Unión a Hierro/genética , Proteínas de Unión a Hierro/metabolismo , Longevidad/efectos de los fármacos , Longevidad/genética , Masculino , Malondialdehído/metabolismo , Actividad Motora/genética , Interferencia de ARN , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , FrataxinaRESUMEN
Usando seis diferentes probes de cromossomo X, estimou-se a freqüência de polimorfismo de comprimento de fragmento de restriçäo (RFLP) com endonucleases de restriçäo em pessoas näo parentes, em uma populaçäo espanhola de Valência. As freqüências de alelos foram semelhantes às de outras populaçöes européias, em particular francesas e turcas. Um alto grau de polimorfismo foi encontrado para todos os marcadores, sendo que a freqüência do alelo raro variou de 0,484 a 0,357 e um alto nível de heterozigose dos marcadores L1.28, 754, OTC e p58.1 foi encontrado nesta populaçäo, confirmando sua utilidade para a diagnose.