Phagocytosis and self-destruction break down dendrites of Drosophila sensory neurons at distinct steps of Wallerian degeneration.
Phagocytosis and self-destruction break down dendrites of Drosophila sensory neurons at distinct steps of Wallerian degeneration.
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DOI：
10.1073/pnas.2111818119
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发表时间：
2022-01-25
影响因子：
11.1
通讯作者：
Han C
中科院分区：
文献类型：
--
作者：
Ji H;Sapar ML;Sarkar A;Wang B;Han C
烟酰胺腺嘌呤二核苷酸(NAD+)生物合成途径的突变与进行性神经变性有关；神经元损伤会导致受损轴突和树突的快速分解。NAD+减少被认为是通过诱导神经元自毁而导致这两种类型的退行性变的基础。在这里，我们表明吞噬作用，而不是自我破坏，在损伤和遗传NAD+中断中驱动果蝇感觉树突的退化。从机制上讲，由于磷脂酰丝氨酸暴露在树突表面，这些操作导致吞噬作用早于自毁。此外，受损的树突表现出独特的钙动力学，仅部分需要轴突死亡因子来自我摧毁。因此，我们的结果表明吞噬作用在NAD+相关的神经退行性疾病中起着重要作用，并强调了树突和轴突退变之间的差异。损伤后，切断的树突和轴突在分解时暴露出其表面的“吃我”信号磷脂酰丝氨酸(PS)。损伤轴突的退行性变受保守的沃勒变性(Weller deAge，WD)途径控制，WD途径被认为是通过Sarm介导的烟酰胺腺嘌呤二核苷酸(NAD+)耗竭激活轴突的自我破坏。虽然已知轴突PS暴露受到NAD+基因操作的影响，但WD途径如何协调轴突PS暴露和自毁，以及PS诱导的吞噬作用是否有助于体内轴突破裂仍不清楚。在这里，我们证明了在果蝇的感觉树突中，PS暴露和自毁是由Sarm激活导致的WD的两个连续步骤。令人惊讶的是，吞噬作用是由遗传NAD+中断和损伤引起的树突退化的主要驱动因素。然而，与神经元Nmnat丢失不同，Nmnat丢失只触发PS暴露并导致吞噬依赖的树突退化，而损伤激活PS暴露和自我破坏作为树突退化的两种多余手段。此外，被砍掉的轴突死亡因子只是受损树突自毁所需的一部分，与PS诱导的吞噬作用平行。最后，受损的树突表现出与WD相关的独特的节律性钙闪烁。因此，在体内损伤诱导的树突变性中，NAD+相关的一般机制和树突特异性程序共同控制PS的暴露和自我破坏。
Mutations in the nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway are associated with progressive neurodegeneration; neuronal injury causes rapid breakdown of damaged axons and dendrites. NAD+ reduction is thought to underlie both types of degeneration by inducing neuronal self-destruction. Here, we show that phagocytosis, instead of self-destruction, drives degeneration of Drosophila sensory dendrites in both injury and genetic NAD+ disruptions. Mechanistically, phagocytosis is induced earlier than self-destruction by these manipulations, as a result of phosphatidylserine exposure on the dendrite surface. In addition, injured dendrites exhibit unique calcium dynamics and only partially require the axon-death factor Axed for self-destruction. Thus, our results suggest important contributions of phagocytosis to NAD+-related neurodegenerative diseases and highlight the difference between dendrite and axon degeneration. After injury, severed dendrites and axons expose the “eat-me” signal phosphatidylserine (PS) on their surface while they break down. The degeneration of injured axons is controlled by a conserved Wallerian degeneration (WD) pathway, which is thought to activate neurite self-destruction through Sarm-mediated nicotinamide adenine dinucleotide (NAD+) depletion. While neurite PS exposure is known to be affected by genetic manipulations of NAD+, how the WD pathway coordinates both neurite PS exposure and self-destruction and whether PS-induced phagocytosis contributes to neurite breakdown in vivo remain unknown. Here, we show that in Drosophila sensory dendrites, PS exposure and self-destruction are two sequential steps of WD resulting from Sarm activation. Surprisingly, phagocytosis is the main driver of dendrite degeneration induced by both genetic NAD+ disruptions and injury. However, unlike neuronal Nmnat loss, which triggers PS exposure only and results in phagocytosis-dependent dendrite degeneration, injury activates both PS exposure and self-destruction as two redundant means of dendrite degeneration. Furthermore, the axon-death factor Axed is only partially required for self-destruction of injured dendrites, acting in parallel with PS-induced phagocytosis. Lastly, injured dendrites exhibit a unique rhythmic calcium-flashing that correlates with WD. Therefore, both NAD+-related general mechanisms and dendrite-specific programs govern PS exposure and self-destruction in injury-induced dendrite degeneration in vivo.
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影响因子：
12.4
作者：
通讯作者：
--
DOI：
10.1083/jcb.200808042
发表时间：
2009-02-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Avery MA;Sheehan AE;Kerr KS;Wang J;Freeman MR
通讯作者：
Freeman MR
影响因子：
8.8
作者：
Bratkowski, Matthew;Xie, Tian;Sambashivan, Shilpa
通讯作者：
Sambashivan, Shilpa
影响因子：
7.7
作者：
Akbergenova Y;Cunningham KL;Zhang YV;Weiss S;Littleton JT
通讯作者：
Littleton JT
影响因子：
48
作者：
Kim, Yujin E.;Chen, Jeannie;Chan, Jonah R.;Langen, Ralf
通讯作者：
Langen, Ralf