Copper overload and deficiency both adversely affect the central nervous system of Drosophila
Copper overload and deficiency both adversely affect the central nervous system of Drosophila
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DOI：
10.1039/c4mt00140k
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发表时间：
2014-01-01
期刊：
影响因子：
3.4
通讯作者：
Burke, Richard
中科院分区：
文献类型：
--
作者：
Hwang, Joab E. C.;de Bruyne, Marinus;Burke, Richard
人类铜稳态障碍Menkes和Wilson病都有严重的神经系统症状。Menkes是一种铜缺乏症，而威尔逊病患者患有铜毒性，这表明严格控制神经元铜水平对神经系统的正常发育和功能至关重要。在这里，我们研究的后果，神经元铜缺乏和过量的果蝇神经系统，使用有针对性的操作的铜吸收基因Ctr1A和Ctr1B和外排基因ATP 7结合改变饮食铜水平。我们发现Ctr1B和ATP 7的泛神经元过度表达都导致活力降低。Ctr1B过表达的影响加剧了饮食中的铜补充和铜限制表明铜毒性表型获救。饮食操作对ATP 7过表达具有相反的作用，表明这会导致由于过量铜流出而导致神经元铜缺乏。铜缺乏还导致存活的成年果蝇的高度渗透性发育缺陷，这可以通过铜过量和铜缺乏特异性针对一小部分神经肽能细胞来复制。我们的结论是，铜超载和过量对果蝇神经元功能有不利影响，降低整体苍蝇的生存能力，以及对特定的神经肽通路的影响。
The human copper homeostasis disorders Menkes and Wilson disease both have severe neurological symptoms. Menkes is a copper deficiency disorder whereas Wilson disease patients suffer from copper toxicity, indicating that tight control of neuronal copper levels is essential for proper nervous system development and function. Here we examine the consequences of neuronal copper deficiency and excess in the Drosophila melanogaster nervous system, using targeted manipulation of the copper uptake genes Ctr1A and Ctr1B and efflux gene ATP7 in combination with altered dietary copper levels. We find that pan-neuronal over expression of Ctr1B and ATP7 both result in a reduction in viability. The effects of Ctr1B over expression are exacerbated by dietary copper supplementation and rescued by copper limitation indicating a copper toxicity phenotype. Dietary manipulation has the opposite effect on ATP7 over expression, indicating that this causes neuronal copper deficiency due to excessive copper efflux. Copper deficiency also causes a highly penetrant developmental defect in surviving adult flies which can be replicated by both copper excess and copper deficiency targeted specifically to a small subset of neuropeptidergic cells. We conclude that both copper overload and excess have detrimental effects on Drosophila neuronal function, reducing overall fly viability as well as impacting on a specific neuropeptide pathway.