ABSTRACT

Human polyglutamine [poly(Q)] disorders such as Huntington's disease, different types of ataxias, etc. are devastating brain illnesses which are characterised by the presence of neurotoxic protein aggregates in the affected neurons. We have recently reported that S6K/4E-BP mediated growth promoting branch of insulin signalling pathway alleviates human poly(Q) induced neurotoxicity in Drosophila disease models.

Objective and Methods

Since, the S6K/4E-BP sub-pathway can be stimulated by various amino acids; we extended our investigation to examine if oral feeding of amino acids delivers rescue against human poly(Q) toxicity in Drosophila. We utilised Drosophila models of two different poly(Q) disorders to test our hypothesis. Glutamine was fed to the test flies orally mixed in the food. Control and treated flies were then tested for different parameters, such as formation of poly(Q) aggregates and neurodegeneration, to evaluate glutamine’s proficiency in mitigating poly(Q) neurotoxicity.

Results

Our study, for the first time, reports that glutamine feeding stimulates the growth promoting S6K/4E-BP branch of insulin signalling pathway and restricts pathogenesis of poly(Q) disorders in Drosophila disease models. We noted that glutamine treatment restricts the formation of neurotoxic poly(Q) aggregates and minimises neuronal deaths. Further, glutamine treatment re-establishes the chromatin architecture by improving the histone acetylation which is otherwise compromised in poly(Q) expressing neuronal cells.

Discussion

Since, the insulin signalling pathway as well as mechanism of action of glutamine are fairly conserved between human and Drosophila, our finding strongly suggests that glutamine holds immense potential to be developed as an intervention therapy against the incurable human poly(Q) disorders.

中文翻译：

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谷氨酰胺刺激胰岛素信号通路的 S6K/4E-BP 分支以减轻果蝇疾病模型中的人类多聚 (Q) 疾病

摘要

人类多聚谷氨酰胺[poly(Q)]疾病，例如亨廷顿病、不同类型的共济失调等，是毁灭性的脑部疾病，其特征是受影响的神经元中存在神经毒性蛋白聚集体。我们最近报道，S6K/4E-BP 介导的胰岛素信号通路的生长促进分支减轻了果蝇疾病模型中人聚 (Q) 诱导的神经毒性。

目的和方法

由于S6K/4E-BP子通路可以被多种氨基酸刺激；我们扩展了我们的研究范围，以检查口服氨基酸是否可以缓解果蝇体内的人类多聚（Q）毒性。我们利用两种不同的多聚（Q）疾病的果蝇模型来检验我们的假设。将谷氨酰胺混入食物中喂给测试果蝇。然后测试对照和治疗果蝇的不同参数，例如聚（Q）聚集体的形成和神经变性，以评估谷氨酰胺减轻聚（Q）神经毒性的能力。

结果

我们的研究首次报道，在果蝇疾病模型中，谷氨酰胺喂养可刺激胰岛素信号通路的促生长 S6K/4E-BP 分支，并限制多聚 (Q) 疾病的发病机制。我们注意到，谷氨酰胺治疗限制了神经毒性聚（Q）聚集体的形成，并最大限度地减少了神经元死亡。此外，谷氨酰胺处理通过改善组蛋白乙酰化来重建染色质结构，否则在表达 Poly(Q) 的神经元细胞中组蛋白乙酰化会受到损害。

讨论

由于胰岛素信号通路以及谷氨酰胺的作用机制在人类和果蝇之间相当保守，我们的发现强烈表明谷氨酰胺具有开发作为针对无法治愈的人类多聚（Q）疾病的干预疗法的巨大潜力。