A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.
A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.
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DOI：
10.1038/cdd.2014.164
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发表时间：
2015-05
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
作者：
NAD代谢调节多种生物过程，包括衰老、昼夜节律和轴突存活。轴突依赖于NAD生物合成中的中心酶，烟酰胺单核苷酸腺苷酰转移酶2（NMNAT2）的活性来维持它们，并且当这种活性丧失时迅速退化。然而，轴突的存活是否受NAD的供应或这种酶的另一种作用的调节仍不清楚。在这里，我们表明，核苷酸前体的NAD，烟酰胺单核苷酸（NMN），积累神经损伤后，促进轴突变性。NMN合成酶NAMPT的抑制剂尽管降低了NAD，但仍对受损的轴突和突触提供了强大的形态和功能保护。外源性NMN废除了这种保护，这表明NMNAT2降解后轴突内的NMN积累可以促进变性。NMN脱酰胺酶（一种细菌NMN清除酶）的异位表达可抑制受损轴突的存活，为支持这一机制提供了遗传学证据。NMN在变性之前升高，NAMPT抑制剂FK 866和轴突保护蛋白WldS都阻止这种升高。这些数据表明，NMNAT和相关的WldS蛋白促进轴突存活的机制是通过限制NMN积累。它们表明了NMN在哺乳动物中的一种新的生理功能，并揭示了癌症化疗新策略与轴突病治疗之间的意外联系。
NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein WldS prevent this rise. These data indicate that the mechanism by which NMNAT and the related WldS protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies.
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影响因子：
3.4
作者：
Adalbert, R;Gillingwater, TH;Coleman, MP
通讯作者：
Coleman, MP
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
DOI：
10.1523/jneurosci.4065-10.2011
发表时间：
2011-01-19
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Barrientos SA;Martinez NW;Yoo S;Jara JS;Zamorano S;Hetz C;Twiss JL;Alvarez J;Court FA
通讯作者：
Court FA
影响因子：
9.2
作者：
Avery, Michelle A;Rooney, Timothy M;Pandya, Jignesh D;Wishart, Thomas M;Gillingwater, Thomas H;Geddes, James W;Sullivan, Patrick G;Freeman, Marc R
通讯作者：
Freeman, Marc R
影响因子：
4.7
作者：
Bi J;Li H;Ye SQ;Ding S
通讯作者：
Ding S