SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration.
SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration.
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DOI：
10.1016/j.neuron.2021.02.009
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发表时间：
2021-04-07
期刊：
影响因子：
16.2
通讯作者：
Ve T
中科院分区：
文献类型：
--
作者：
Figley MD;Gu W;Nanson JD;Shi Y;Sasaki Y;Cunnea K;Malde AK;Jia X;Luo Z;Saikot FK;Mosaiab T;Masic V;Holt S;Hartley-Tassell L;McGuinness HY;Manik MK;Bosanac T;Landsberg MJ;Kerry PS;Mobli M;Hughes RO;Milbrandt J;Kobe B;DiAntonio A;Ve T
轴突变性是许多神经退行性疾病的中心病理特征。SARM 1是一种NAD+裂解酶，其激活触发轴突破坏。生物合成酶NMNAT 2（将烟酰胺单核苷酸（NMN）转化为NAD+）的缺失通过未知机制激活SARM 1。使用结构，生物化学，生物物理和细胞分析，我们证明，SARM 1被激活的NMN NAD+的比例增加，并显示，这两种代谢物竞争结合到SARM 1的自抑制性N-末端ARM结构域。我们报告的SARM 1 ARM结构域结合NMN和同源八聚体SARM 1复合物的配体的情况下的结构。我们表明，NMN的影响SARM 1的结构，并通过诱变证明，NMN结合损伤诱导的SARM 1激活和轴突破坏所需的。因此，SARM 1是一种代谢传感器，通过切割残留的NAD+来响应增加的NMN/NAD+比率，从而诱导前馈代谢灾难和轴突死亡。Figley等人证明，SARM 1是一种诱导型前变性NAD酶，是一种通过NMN/NAD+比率增加而激活的代谢传感器。作者提供了对SARM 1调控的结构和功能见解，这扩展了我们对SARM 1作为可药物靶点的理解，并对广泛的神经退行性疾病产生了影响。
Axon degeneration is a central pathological feature of many neurodegenerative diseases. SARM1 is an NAD+-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD+, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD+, and show that both metabolites compete for binding to the auto-inhibitory N-terminal ARM domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feed-forward metabolic catastrophe and axonal demise. Figley et al. demonstrate that SARM1, an inducible pro-degenerative NADase, is a metabolic sensor activated by an increase in the NMN/NAD+ ratio. The authors provide structural and functional insights into SARM1 regulation, which expands our understanding of SARM1 as a druggable target, with implications for a wide-range of neurodegenerative diseases.