Overexpression of human and fly frataxins in Drosophila provokes deleterious effects at biochemical, physiological and developmental levels.
Overexpression of human and fly frataxins in Drosophila provokes deleterious effects at biochemical, physiological and developmental levels.
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DOI：
10.1371/journal.pone.0021017
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Moltó MD
中科院分区：
文献类型：
--
作者：
Navarro JA;Llorens JV;Soriano S;Botella JA;Schneuwly S;Martínez-Sebastián MJ;Moltó MD
弗里德赖希共济失调（FA）是高加索人群中最常见的遗传性共济失调形式，是由高度保守的共济失调蛋白（frataxin）表达减少引起的。模式生物在破译frataxin功能的努力中做出了巨大贡献;然而，这种蛋白质的精确功能仍然难以捉摸。过表达研究是一个有用的方法来调查的frataxin的机制作用，然而，现有的文献报道相互矛盾的结果。为了进一步研究共济失调蛋白过表达的影响，我们分析了在果蝇中过表达人（FXN）和蝇（FH）共济失调蛋白的后果。 我们使用UAS-GAL 4系统获得了在一般模式和不同组织中过表达人或苍蝇frataxins的转基因苍蝇。对于这两种fraataxins，我们观察到有害的影响，在生化，组织学和行为水平。氧化应激是共济失调蛋白过度表达表型的相关因素。系统性共济失调蛋白过度表达降低果蝇的生存能力，并损害肌肉和周围神经系统的正常胚胎发育。在过表达共济失调蛋白的转基因果蝇中也观察到顺乌头酸酶活性水平的降低和NDUF 3水平的降低。神经系统中的共济失调蛋白过度表达会缩短寿命，损害运动能力并导致脑退化。已证明Frataxin聚集和该蛋白质的错误折叠不是导致观察到的表型的机制。然而，人共济失调蛋白的表达挽救了fh敲低突变体中的顺乌头酸酶活性。我们的研究结果提供了体内证据的功能等效的人类和苍蝇fraataxins，并表明，fraataxin表达的控制是重要的治疗，旨在增加fraataxin水平。
Friedreich's ataxia (FA), the most frequent form of inherited ataxias in the Caucasian population, is caused by a reduced expression of frataxin, a highly conserved protein. Model organisms have contributed greatly in the efforts to decipher the function of frataxin; however, the precise function of this protein remains elusive. Overexpression studies are a useful approach to investigate the mechanistic actions of frataxin; however, the existing literature reports contradictory results. To further investigate the effect of frataxin overexpression, we analyzed the consequences of overexpressing human (FXN) and fly (FH) frataxins in Drosophila. We obtained transgenic flies that overexpressed human or fly frataxins in a general pattern and in different tissues using the UAS-GAL4 system. For both frataxins, we observed deleterious effects at the biochemical, histological and behavioral levels. Oxidative stress is a relevant factor in the frataxin overexpression phenotypes. Systemic frataxin overexpression reduces Drosophila viability and impairs the normal embryonic development of muscle and the peripheral nervous system. A reduction in the level of aconitase activity and a decrease in the level of NDUF3 were also observed in the transgenic flies that overexpressed frataxin. Frataxin overexpression in the nervous system reduces life span, impairs locomotor ability and causes brain degeneration. Frataxin aggregation and a misfolding of this protein have been shown not to be the mechanism that is responsible for the phenotypes that have been observed. Nevertheless, the expression of human frataxin rescues the aconitase activity in the fh knockdown mutant. Our results provide in vivo evidence of a functional equivalence for human and fly frataxins and indicate that the control of frataxin expression is important for treatments that aim to increase frataxin levels.
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影响因子：
3.5
作者：
Anderson, PR;Kirby, K;Phillips, JP
通讯作者：
Phillips, JP
DOI：
10.1073/pnas.252342899
发表时间：
2002-12-10
影响因子：
11.1
作者：
Kirby, K;Hu, JG;Phillips, JP
通讯作者：
Phillips, JP
影响因子：
4.1
作者：
Das, N;Levine, RL;Sohal, RS
通讯作者：
Sohal, RS
影响因子：
4.8
作者：
Layer, Gunhild;Ollagnier-de Choudens, Sandrine;Fontecave, Marc
通讯作者：
Fontecave, Marc
影响因子：
7.7
作者：
Aloria, K;Schilke, B;Craig, EA
通讯作者：
Craig, EA