A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity.
A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity.
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DOI：
10.1016/j.cub.2012.01.065
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发表时间：
2012-04-10
期刊：
影响因子：
9.2
通讯作者：
Bonini, Nancy M
中科院分区：
文献类型：
--
作者：
Fang, Yanshan;Soares, Lorena;Teng, Xiuyin;Geary, Melissa;Bonini, Nancy M
因急性损伤、毒性损伤或神经退行性疾病而受损的轴突会发生华勒变性或类华勒变性，这是一个活跃且有序的细胞过程，但其潜在机制尚不清楚。果蝇已被证明是模拟人类神经退行性疾病的成功系统。在这项研究中，我们利用成年果蝇翅膀建立了一种新型的轴突损伤体内模型。荧光蛋白标记物突出显示的翼神经可以在活体动物中直接可视化，并且通过简单的翅膀切割即可精确切断，使其非常适合大规模筛查。使用该模型，我们证实了 Wlds 和 Nmnat 的轴突保护功能。我们进一步揭示，内源性 Nmnat 的敲低会引发体内自发的、死亡性的轴突变性。有趣的是，轴突线粒体在轴突切除或 Nmnat 下调后迅速耗尽。 Nmnat 的上调显着抑制了损伤引起的线粒体损失，这也保护了切断的轴突免于退化。然而，当线粒体从轴突中被基因消除时，Nmnat 的上调不再有效抑制轴突变性。总之，这些发现证明了内源性 Nmnat 在维持轴突完整性方面的重要作用，轴突完整性可能依赖于稳定线粒体并通过稳定线粒体发挥作用。
Axons damaged by acute injury, toxic insults or during neurodegenerative diseases undergo Wallerian or Wallerian-like degeneration, which is an active and orderly cellular process but the underlying mechanisms are poorly understood. Drosophila has been proven a successful system for modeling human neurodegenerative diseases. In this study, we established a novel in vivo model of axon injury using the adult fly wing. The wing nerve highlighted by fluorescent protein markers can be directly visualized in living animals and be precisely severed by a simple wing cut, making it highly suitable for large-scale screening. Using this model, we confirmed an axonal protective function of Wlds and Nmnat. We further revealed that knockdown of endogenous Nmnat triggered spontaneous, dying-back axon degeneration in vivo. Intriguingly, axonal mitochondria were rapidly depleted upon axotomy or downregulation of Nmnat. The injury-induced mitochondrial loss was dramatically suppressed by upregulation of Nmnat, which also protected severed axons from degeneration. However, when mitochondria were genetically eliminated from axons, upregulation of Nmnat was no longer effective to suppress axon degeneration. Together, these findings demonstrate an essential role of endogenous Nmnat in maintaining axonal integrity that may rely on and function by stabilizing mitochondria.