AKT-sensitive or insensitive pathways of toxicity in glial cells and neurons in Drosophila models of Huntington's disease
AKT-sensitive or insensitive pathways of toxicity in glial cells and neurons in Drosophila models of Huntington's disease
复制标题
DOI：
10.1093/hmg/ddm360
复制
发表时间：
2008-03-15
影响因子：
3.5
通讯作者：
Birman, Serge
中科院分区：
文献类型：
--
作者：
Lievens, Jean-Charles;Iche, Magali;Birman, Serge
亨廷顿氏病（HD）是由亨廷顿蛋白中延伸的多聚谷氨酰胺（polyQ）道引起的。神经元和胶质细胞功能障碍先于神经变性，似乎是HD早期症状的主要原因。近年来，果蝇polyQ相关疾病模型的开发促进了候选救援基因的研究。在大多数情况下，通过评估对视网膜和/或脑神经元的毒性进行果蝇分析。然而，没有一个潜在的挽救者被评估神经胶质的改变。在这里，我们使用了遗传学的方法在果蝇表征突变亨廷顿蛋白（mHtt）在神经元或不同的神经胶质细胞亚群中表达的表型效应，我们建立了一个敏感的测定评估神经胶质细胞改变的修饰剂。我们确定了通过激活视网膜中的AKT和ERK抗凋亡激酶以及果蝇大脑的神经元和神经胶质细胞来确保细胞保护的水平，并与HSP 70伴侣的拯救效果进行了比较。我们发现AKT和HSP 70都减轻了mHtt诱导的视网膜毒性。相反，它们在大脑中的保护作用不同。HSP 70挽救了在神经元或神经胶质中表达mHtt的果蝇的神经变性、运动缺陷和早期致死性。AKT不能阻止果蝇的脑神经元死亡和致死性，但当与mHtt在胶质细胞中共表达时，显著改善了它们的运动性能。ERK在视网膜或大脑中没有有益的作用。这些结果表明，mHtt激活果蝇中不同的毒性途径，在视网膜光感受器和神经胶质细胞中对AKT敏感，或在脑神经元中独立。
Huntington's disease (HD) is caused by an extended polyglutamine (polyQ) tract in the Huntingtin protein. Neuronal and glial dysfunction precedes the neurodegeneration and appears to be the primary cause for the early symptoms in HD. In recent years, development of Drosophila models of polyQ-related diseases facilitated research of candidate rescuer genes. In most cases, analysis in Drosophila was performed by assessing toxicity on retinal and/or brain neurons. However, none of the potential rescuers were evaluated on glial alterations. Here we used a genetic approach in Drosophila to characterize the phenotypic effects of mutant Huntingtin (mHtt) expressed in neurons or different glia subsets and we established a sensitive assay for evaluating modifiers of glial alterations. We determined the level of cell protection ensured by activation of the AKT and ERK anti-apoptotic kinases in the retina as well as in neurons and glia of the fly brain, compared with the rescuing effects of the HSP70 chaperone. We found that both AKT and HSP70 alleviated mHtt-induced toxicity in the retina. In contrast, their protective effects differed in the brain. HSP70 rescued neurodegeneration, locomotor defects and early lethality of flies expressing mHtt in neurons or glia. AKT failed to prevent brain neuronal death and lethality of flies, but significantly improved their locomotor performance when co-expressed with mHtt in glia. ERK had no beneficial effects in the retina or brain. These results indicate that mHtt activates distinct pathways of toxicity in Drosophila, either sensitive to AKT in retinal photoreceptors and glia, or independent in brain neurons.