Gilley Jonathan, Orsomando Giuseppe, Nascimento-Ferreira Isabel, Coleman Michael P
Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy.
Cell Rep. 2015 Mar 31;10(12):1974-81. doi: 10.1016/j.celrep.2015.02.060. Epub 2015 Mar 26.
SARM1 function and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) loss both promote axon degeneration, but their relative relationship in the process is unknown. Here, we show that NMNAT2 loss and resultant changes to NMNAT metabolites occur in injured SARM1-deficient axons despite their delayed degeneration and that axon degeneration specifically induced by NMNAT2 depletion requires SARM1. Strikingly, SARM1 deficiency also corrects axon outgrowth in mice lacking NMNAT2, independently of NMNAT metabolites, preventing perinatal lethality. Furthermore, NAMPT inhibition partially restores outgrowth of NMNAT2-deficient axons, suggesting that the NMNAT substrate, NMN, contributes to this phenotype. NMNAT2-depletion-dependent degeneration of established axons and restricted extension of developing axons are thus both SARM1 dependent, and SARM1 acts either downstream of NMNAT2 loss and NMN accumulation in a linear pathway or in a parallel branch of a convergent pathway. Understanding the pathway will help establish relationships with other modulators of axon survival and facilitate the development of effective therapies for axonopathies.
甾体激素受体调节剂1（SARM1）的功能以及烟酰胺单核苷酸腺苷酸转移酶2（NMNAT2）的缺失均会促进轴突退化，但其在此过程中的相对关系尚不清楚。在此，我们表明，尽管SARM1缺陷的轴突退化延迟，但在受损的SARM1缺陷轴突中仍会发生NMNAT2缺失以及由此导致的NMNAT代谢产物变化，并且由NMNAT2耗竭特异性诱导的轴突退化需要SARM1。令人惊讶的是，SARM1缺陷还能纠正缺乏NMNAT2的小鼠的轴突生长，且与NMNAT代谢产物无关，从而防止围产期致死。此外，烟酰胺磷酸核糖转移酶（NAMPT）抑制可部分恢复NMNAT2缺陷轴突的生长，这表明NMNAT的底物NMN促成了这一表型。因此，已建立轴突的NMNAT – 2缺失依赖性退化以及发育中轴突的受限延伸均依赖于SARM1，并且SARM1要么在NMNAT2缺失和NMN积累的线性途径的下游起作用，要么在汇聚途径的平行分支中起作用。了解该途径将有助于建立与轴突存活的其他调节因子的关系，并促进轴突病有效疗法的开发。
