Sarm1 haploinsufficiency or low expression levels after antisense oligonucleotides delay programmed axon degeneration.
Sarm1 haploinsufficiency or low expression levels after antisense oligonucleotides delay programmed axon degeneration.
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DOI：
10.1016/j.celrep.2021.110108
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发表时间：
2021-12-14
期刊：
影响因子：
8.8
通讯作者：
Coleman M
中科院分区：
文献类型：
--
作者：
Gould SA;Gilley J;Ling K;Jafar-Nejad P;Rigo F;Coleman M
在各种身体和疾病相关损伤后，促变性蛋白SARM 1的激活导致程序性轴突变性。最初的研究表明，神经保护需要大幅降低SARM 1水平。然而，我们证明，在SARM 1单倍不足的小鼠，降低SARM 1水平的50%延迟程序性轴突变性后，坐骨神经横断在体内，并部分防止神经突生长缺陷缺乏促生存因子NMNAT2的小鼠。在体外，响应于SARM 1激活的创伤性、神经毒性和遗传触发的变性速率也减慢。最后，我们证明了Sarm1反义寡核苷酸在体外将SARM 1水平降低了50%以上，这延迟或防止了程序性轴突变性。将SARM 1单倍不足与反义寡核苷酸组合进一步降低SARM 1水平和神经毒性损伤后的神经保护作用。这些数据表明，轴突保护发生在一个SARM 1基因剂量反应的方式和SARM 1降低剂具有治疗潜力，使SARM 1靶向反义寡核苷酸一个有前途的治疗策略。SARM 1依赖性轴突变性发生在不同的神经毒性触发因素后沉默促变性SARM 1的一个等位基因减缓程序性轴突变性SARM 1 ASO可以模拟这一点，在多种情况下延迟轴突变性降低SARM 1表达甚至部分可能具有治疗价值通过降低但不完全去除促变性蛋白SARM 1，Gould et al.在与疼痛障碍、线粒体功能障碍、蛋白质合成受损和NMNAT2破坏相关的模型中延迟轴突变性。使用反义寡核苷酸，他们证明了神经保护而不完全消除SARM 1，加强了SARM 1作为一种可行的治疗方法的价值。
Activation of the pro-degenerative protein SARM1 after diverse physical and disease-relevant injuries causes programmed axon degeneration. Original studies indicate that substantially decreased SARM1 levels are required for neuroprotection. However, we demonstrate, in Sarm1 haploinsufficient mice, that lowering SARM1 levels by 50% delays programmed axon degeneration in vivo after sciatic nerve transection and partially prevents neurite outgrowth defects in mice lacking the pro-survival factor NMNAT2. In vitro, the rate of degeneration in response to traumatic, neurotoxic, and genetic triggers of SARM1 activation is also slowed. Finally, we demonstrate that Sarm1 antisense oligonucleotides decrease SARM1 levels by more than 50% in vitro, which delays or prevents programmed axon degeneration. Combining Sarm1 haploinsufficiency with antisense oligonucleotides further decreases SARM1 levels and prolongs protection after neurotoxic injury. These data demonstrate that axon protection occurs in a Sarm1 gene dose-responsive manner and that SARM1-lowering agents have therapeutic potential, making Sarm1-targeting antisense oligonucleotides a promising therapeutic strategy. SARM1-dependent axon degeneration occurs after diverse neurotoxic triggers Silencing one allele of pro-degenerative SARM1 slows programmed axon degeneration Sarm1 ASOs can mimic this, delaying axon degeneration in multiple contexts Decreasing SARM1 expression even partially may be therapeutically valuable By lowering but not completely removing the pro-degenerative protein SARM1, Gould et al. delay axon degeneration in models relevant to pain disorders, mitochondrial dysfunction, impaired protein synthesis, and NMNAT2 disruption. Using antisense oligonucleotides, they demonstrate neuroprotection without total elimination of SARM1, reinforcing the value of SARM1 as a viable therapeutic approach.
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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：
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通讯作者：
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影响因子：
15.3
作者：
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影响因子：
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作者：
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影响因子：
3.7
作者：
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在ALS和其他运动神经疾病患者中，用组成性多动NADase编码变体的SARM1等位基因富集。
影响因子：
7.7
作者：
Gilley J;Jackson O;Pipis M;Estiar MA;Al-Chalabi A;Danzi MC;van Eijk KR;Goutman SA;Harms MB;Houlden H;Iacoangeli A;Kaye J;Lima L;Queen Square Genomics;Ravits J;Rouleau GA;Schüle R;Xu J;Züchner S;Cooper-Knock J;Gan-Or Z;Reilly MM;Coleman MP
通讯作者：
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