Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons.
Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons.
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DOI：
10.1016/j.nbd.2022.105808
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发表时间：
2022-09
影响因子：
6.1
通讯作者：
Koliatsos, Vassilis E.
中科院分区：
文献类型：
--
作者：
Alexandris, Athanasios S.;Ryu, Jiwon;Rajbhandari, Labchan;Harlan, Robert;McKenney, James;Wang, Yiqing;Aja, Susan;Graham, David;Venkatesan, Arun;Koliatsos, Vassilis E.
沃勒变性是一种保守的轴突自毁程序，与几种神经系统疾病有关。WD是由NAD+合成酶NMNA2的降解、底物NMN的积聚和NAD+降解Sarm1的激活而驱动的，最终导致轴突碎裂。这些事件的调节和对治疗干预的适应性仍不清楚。在此，我们探索了调节NMN和NAD+代谢的药物策略，即在体外轴突切断模型中抑制NMN合成酶NAMPT，激活烟酸核苷(NAR)挽救途径和抑制NMNat2降解DLK MAPK途径。结果表明，NAMPT和DLK抑制引起WD显著延迟，但具有时间依赖性。这些时间依赖效应与NMNA2的降解以及NMN和NAD+水平的变化有关。补充NAMPT抑制与NAR具有增强的效果，不依赖于干预的时间，并导致强大的保护长达4天。额外的DLK抑制作用甚至将这一时间延长到6天。代谢产物分析表明，NAMPT和MAPK抑制通过降低NMN水平、改善NAD+损失和抑制Sarm1活性发挥复杂的作用。最后，轴突NAD+/NMN比率是cADPR水平的高度预测，扩大了先前关于Sarm1变构调节的无细胞证据。我们的发现建立了轴突保护窗口，在损伤后持续几个小时。此外，我们显示，通过联合MAPK和NAMPT抑制的混合处理，通过对NAD+代谢的复杂影响和对Sarm1的抑制，可以延长保护时间。
Wallerian degeneration (WD) is a conserved axonal self-destruction program implicated in several neurological diseases. WD is driven by the degradation of the NAD+ synthesizing enzyme NMNAT2, the buildup of its substrate NMN, and the activation of the NAD+ degrading SARM1, eventually leading to axonal fragmentation. The regulation and amenability of these events to therapeutic interventions remain unclear. Here we explored pharmacological strategies that modulate NMN and NAD+ metabolism, namely the inhibition of the NMN-synthesizing enzyme NAMPT, activation of the nicotinic acid riboside (NaR) salvage pathway and inhibition of the NMNAT2-degrading DLK MAPK pathway in an axotomy model in vitro. Results show that NAMPT and DLK inhibition cause a significant but time-dependent delay of WD. These time-dependent effects are related to NMNAT2 degradation and changes in NMN and NAD+ levels. Supplementation of NAMPT inhibition with NaR has an enhanced effect that does not depend on timing of intervention and leads to robust protection up to 4 days. Additional DLK inhibition extends this even further to 6 days. Metabolite analyses reveal complex effects indicating that NAMPT and MAPK inhibition act by reducing NMN levels, ameliorating NAD+ loss and suppressing SARM1 activity. Finally, the axonal NAD+/NMN ratio is highly predictive of cADPR levels, extending previous cell-free evidence on the allosteric regulation of SARM1. Our findings establish a window of axon protection extending several hours following injury. Moreover, we show prolonged protection by mixed treatments combining MAPK and NAMPT inhibition that proceed via complex effects on NAD+ metabolism and inhibition of SARM1.
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DOI：
10.1038/s41583-020-0269-3
发表时间：
2020-04
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Coleman MP;Höke A
通讯作者：
Höke A
影响因子：
6.1
作者：
Fernandes, Kimberly A.;Harder, Jeffrey M.;Fornarola, Laura B.;Freeman, Robert S.;Clark, Abbot F.;Pang, Iok-Hou;John, Simon W. M.;Libby, Richard T.
通讯作者：
Libby, Richard T.
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
8.8
作者：
Bratkowski, Matthew;Xie, Tian;Sambashivan, Shilpa
通讯作者：
Sambashivan, Shilpa
影响因子：
16.2
作者：
Essuman K;Summers DW;Sasaki Y;Mao X;DiAntonio A;Milbrandt J
通讯作者：
Milbrandt J