Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss.
Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss.
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神经毒素破坏SARM 1的变构激活机制，诱导神经元损失。
DOI：
10.1016/j.celrep.2021.109872
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发表时间：
2021-10-19
期刊：
影响因子：
8.8
通讯作者：
Milbrandt J
中科院分区：
文献类型：
--
作者：
Wu T;Zhu J;Strickland A;Ko KW;Sasaki Y;Dingwall CB;Yamada Y;Figley MD;Mao X;Neiner A;Bloom AJ;DiAntonio A;Milbrandt J
Sarm1是一种可诱导的TIR结构域NAD+水解酶，介导病理性轴突变性。Sarm1通过增加NMN和NAD+的比例来激活，NAD+竞争与变构激活位点的结合。当NMN结合时，TIR结构域从自身抑制中释放出来，激活其NAD+水解酶活性。这个变构激活位点的发现使我们推测，其他与NAD+相关的代谢物也可能激活Sarm1。在这里，我们展示了20世纪40年代首次被鉴定为神经毒素的烟酰胺类似物3-乙酰吡啶(3-AP)被转化为3-APMN，3-APMN激活Sarm1并诱导Sarm1依赖的NAD+耗竭、轴突变性和神经元死亡。在小鼠中，3-AP的全身治疗会导致Sarm1依赖的快速死亡，而局部应用于周围神经则会导致Sarm1依赖的轴突变性。我们鉴定2-氨基吡啶是另一种依赖于Sarm1的神经毒素。这些发现确认Sarm1是环境神经毒性的候选介体，并提示Sarm1激动剂可以发展为神经溶解治疗的选择性药物。Wu等人。识别在神经元中转化为Sarm1变构激活剂的神经毒素，以触发Sarm1依赖的轴突变性和神经细胞死亡。这些发现确认Sarm1是环境神经毒性的候选介体，并提示Sarm1激动剂可以发展为神经溶解治疗的选择性药物。
SARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD+-related metabolites might activate SARM1. Here we show the nicotinamide analogue 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN which activates SARM1 and induces SARM1-dependent NAD+ depletion, axon degeneration and neuronal death. In mice, systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to peripheral nerve induces SARM1-dependent axon degeneration. We identify 2-aminopyridine as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity, and suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy. Wu et al. identify neurotoxins that are converted to SARM1 allosteric activators in neurons to trigger SARM1-dependent axon degeneration and neuronal cell death. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity, and suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy.
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