Single-axon-resolution intravital imaging reveals a rapid onset form of Wallerian degeneration in the adult neocortex
Single-axon-resolution intravital imaging reveals a rapid onset form of Wallerian degeneration in the adult neocortex
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DOI：
10.1101/391425
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发表时间：
2018-08
期刊：
影响因子：
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通讯作者：
A. Canty;J. Jackson;L. Huang;A. Trabalza;C. Bass;G. Little;V. De Paola
中科院分区：
文献类型：
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作者：
A. Canty;J. Jackson;L. Huang;A. Trabalza;C. Bass;G. Little;V. De Paola
尽管轴突变性在受伤和患病的神经系统中广泛发生，但变性过程的机制仍不完全清楚。特别是，调节单个轴突在哺乳动物大脑的原生环境中如何退化的因素尚不清楚。对超过 120 个单独损伤的皮质轴突的纵向成像揭示了一个阈值长度，低于该阈值长度，损伤的轴突会发生快速发生的沃勒变性 (ROWD)。 ROWD 始终比经典沃勒变性 (WD) 早 10 倍启动，执行速度慢 4 倍。与 WD 不同，ROWD 取决于突触密度，但与轴突复杂性无关。最后，我们提供了药理学和遗传学证据，证明烟酰胺腺嘌呤二核苷酸 (NAD+) 依赖性途径控制皮质轴突 ROWD，不依赖于受损神经元的转录。因此，我们的数据重新定义了干预的治疗窗口，以维持受损皮质神经元的神经功能，并支持使用体内光学成像来获得对大脑轴突变性机制的独特见解。
Despite the widespread occurrence of axon degeneration in the injured and diseased nervous system, the mechanisms of the degenerative process remain incompletely understood. In particular, the factors that regulate how individual axons degenerate within their native environment in the mammalian brain are unknown. Longitudinal imaging of >120 individually injured cortical axons revealed a threshold length below which injured axons undergo a rapid-onset form of Wallerian degeneration (ROWD). ROWD consistently starts 10 times earlier and is executed 4 times slower than classic Wallerian degeneration (WD). ROWD is dependent on synaptic density, unlike WD, but is independent of axon complexity. Finally, we provide both pharmacological and genetic evidence that a Nicotinamide Adenine Dinucleotide (NAD+)-dependent pathway controls cortical axon ROWD independent of transcription in the damaged neurons. Thus, our data redefine the therapeutic window for intervention to maintain neurological function in injured cortical neurons, and support the use of in vivo optical imaging to gain unique insights into the mechanisms of axon degeneration in the brain.