Neuronal death in Drosophila triggered by GAL4 accumulation
Neuronal death in Drosophila triggered by GAL4 accumulation
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DOI：
10.1111/j.1460-9568.2007.05317.x
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发表时间：
2007-02-01
影响因子：
3.4
通讯作者：
Ceriani, Maria Fernanda
中科院分区：
文献类型：
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作者：
Rezaval, Carolina;Werbajh, Santiago;Ceriani, Maria Fernanda
GAL4/UAS 系统已广泛应用于果蝇中，以控制特定空间模式的基因表达。最近，该系统已成功应用于表达与神经变性有关的基因，以模拟果蝇的各种疾病。我们使用了在参与节律行为控制的特定神经元亚群中表达不同水平 GAL4 的转基因系，因此它对神经元生理学的影响将导致运动活动的改变，这可以很容易地评估。我们观察到 gal4 剂量与特定表达 GAL4 的神经元中与凋亡神经元损失相关的行为缺陷之间存在显着相关性。 gal4 剂量的增加与不溶性 GAL4 的积累相关，表明导致细胞凋亡的级联事件可能是由 GAL4 或蛋白质中间体的蛋白质沉积触发的。行为缺陷可以通过 hsp70 的表达来挽救，hsp70 是一种经典的伴侣，也会干扰细胞死亡途径。与后者一致的是，病毒 caspase 抑制剂 p35 也挽救了 GAL4 诱导的行为缺陷。我们的观察证明了 GAL4 失调对神经元活力的内在影响，并表明过量的 GAL4 可能会增强神经变性模型中观察到的神经元缺陷。
The GAL4/UAS system has been extensively employed in Drosophila to control gene expression in defined spatial patterns. More recently this system has been successfully applied to express genes involved in neurodegeneration to model various diseases in the fruit fly. We used transgenic lines expressing different levels of GAL4 in a particular subset of neurons involved in the control of rhythmic behaviour, so that its impact on neuronal physiology would result in altered locomotor activity, which could be readily assessed. We observed a striking correlation between gal4 dosage and behavioural defects associated with apoptotic neuronal loss in the specific GAL4-expressing neurons. Increased gal4 dosage correlated with accumulation of insoluble GAL4, suggesting that the cascade of events leading to apoptosis might be triggered by protein deposits of either GAL4 or protein intermediates. Behavioural defects were rescued by expression of hsp70, a classic chaperone that also interferes with cell death pathways. In agreement with the latter, the viral caspase inhibitor p35 also rescued GAL4-induced behavioural defects. Our observations demonstrate the intrinsic effects of GAL4 deregulation on neuronal viability and suggest that an excess of GAL4 might enhance neuronal deficits observed in models of neurodegeneration.