Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA, USA.
Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA, USA.
Neuron. 2017 Jul 5;95(1):78-91.e5. doi: 10.1016/j.neuron.2017.06.031.
Axon degeneration is a hallmark of neurodegenerative disease and neural injury. Axotomy activates an intrinsic pro-degenerative axon death signaling cascade involving loss of the NAD biosynthetic enzyme Nmnat/Nmnat2 in axons, activation of dSarm/Sarm1, and subsequent Sarm-dependent depletion of NAD. Here we identify Axundead (Axed) as a mediator of axon death. axed mutants suppress axon death in several types of axons for the lifespan of the fly and block the pro-degenerative effects of activated dSarm in vivo. Neurodegeneration induced by loss of the sole fly Nmnat ortholog is also fully blocked by axed, but not dsarm, mutants. Thus, pro-degenerative pathways activated by dSarm signaling or Nmnat elimination ultimately converge on Axed. Remarkably, severed axons morphologically preserved by axon death pathway mutations remain integrated in circuits and able to elicit complex behaviors after stimulation, indicating that blockade of axon death signaling results in long-term functional preservation of axons.
轴突变性是神经退行性疾病和神经损伤的标志。轴突切断激活了内在的促变性轴突死亡信号级联反应，涉及轴突中 NAD 生物合成酶 Nmnat/Nmnat2 的丧失、dSarm/Sarm1 的激活以及随后 Sarm 依赖性 NAD 耗竭。在这里，我们确定 Axundead（Axed）为轴突死亡的介质。在果蝇的整个生命周期中，axed 突变体抑制了几种类型的轴突死亡，并阻断了体内激活的 dSarm 的促变性作用。唯一的果蝇 Nmnat 同源物缺失引起的神经退行性变也被 axed 突变体完全阻断，但 dsarm 突变体没有。因此，由 dSarm 信号或 Nmnat 消除激活的促变性途径最终汇集到 Axed。值得注意的是，通过轴突死亡途径突变形态上保存的切断轴突仍然整合在回路中，并能够在刺激后产生复杂的行为，这表明阻断轴突死亡信号导致轴突的长期功能保存。
