SARM1 Depletion Slows Axon Degeneration in a CNS Model of Neurotropic Viral Infection.
SARM1 Depletion Slows Axon Degeneration in a CNS Model of Neurotropic Viral Infection.
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DOI：
10.3389/fnmol.2022.860410
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发表时间：
2022
影响因子：
4.8
通讯作者：
Edgar, Julia M.
中科院分区：
文献类型：
--
作者：
Crawford, Colin L.;Antoniou, Christina;Komarek, Lina;Schultz, Verena;Donald, Claire L.;Montague, Paul;Barnett, Susan C.;Linington, Christopher;Willison, Hugh J.;Kohl, Alain;Coleman, Michael P.;Edgar, Julia M.
寨卡病毒 (ZIKV) 是一种嗜神经性黄病毒，最近与儿童先天性寨卡病毒综合征以及成人脑炎和吉兰-巴雷综合征有关。嗜神经病毒通常使用轴突运输到神经元或神经胶质细胞体，在那里它们要么保持潜伏，要么复制并继续感染新细胞。因此，有人认为轴突变性可能代表了一种限制病毒传播的进化保守机制。虽然尚不清楚 ZIKV 是否在轴突中传播，但我们之前报道过，在小鼠脊髓源性中枢神经系统细胞培养模型中，ZIKV 感染神经胶质细胞与神经元细胞过程的严重丧失有关。尽管有丝分裂后神经元相对不易感染和死亡。在这里，我们测试了这样的假设：ZIKV 相关的神经元过程变性依赖于不育 α 和犰狳基序含有蛋白 1 (SARM1) 的激活，SARM1 是一种 NADase，在保守的轴突变性途径中充当中央刽子手。为了测试这一点，我们用 ZIKV 感染野生型和 Sarm1 纯合或杂合零细胞培养物，并检查 NAD+ 水平以及神经元及其过程的存活情况。出乎意料的是，ZIKV 感染导致 NAD+ 不依赖于 SARM1 快速减少。尽管如此，随后神经元细胞过程的严重丧失是 SARM1 依赖性的，并且先于 β-微管蛋白 III 染色外观的早期变化。总之，这些数据确定了 SARM1 在 ZIKV 感染发病机制中的作用，这可能反映了 SARM1 保守的促退行性功能，与其 NADase 活性无关。
Zika virus (ZIKV) is a neurotropic flavivirus recently linked to congenital ZIKV syndrome in children and encephalitis and Guillain-Barré syndrome in adults. Neurotropic viruses often use axons to traffic to neuronal or glial cell somas where they either remain latent or replicate and proceed to infect new cells. Consequently, it has been suggested that axon degeneration could represent an evolutionarily conserved mechanism to limit viral spread. Whilst it is not known if ZIKV transits in axons, we previously reported that ZIKV infection of glial cells in a murine spinal cord-derived cell culture model of the CNS is associated with a profound loss of neuronal cell processes. This, despite that postmitotic neurons are relatively refractory to infection and death. Here, we tested the hypothesis that ZIKV-associated degeneration of neuronal processes is dependent on activation of Sterile alpha and armadillo motif-containing protein 1 (SARM1), an NADase that acts as a central executioner in a conserved axon degeneration pathway. To test this, we infected wild type and Sarm1 homozygous or heterozygous null cell cultures with ZIKV and examined NAD+ levels as well as the survival of neurons and their processes. Unexpectedly, ZIKV infection led to a rapid SARM1-independent reduction in NAD+. Nonetheless, the subsequent profound loss of neuronal cell processes was SARM1-dependent and was preceded by early changes in the appearance of β-tubulin III staining. Together, these data identify a role for SARM1 in the pathogenesis of ZIKV infection, which may reflect SARM1's conserved prodegenerative function, independent of its NADase activity.
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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：
Coleman MP;Höke A
通讯作者：
Höke A
影响因子：
7.4
作者：
Baxter, Paul S.;Hardingham, Giles E.
通讯作者：
Hardingham, Giles E.
影响因子：
29
作者：
Ferreira da Silva, Ivan Rocha;Frontera, Jennifer A.;Moreira do Nascimento, Osvaldo Jose
通讯作者：
Moreira do Nascimento, Osvaldo Jose
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
7.1
作者：
Cumberworth SL;Barrie JA;Cunningham ME;de Figueiredo DPG;Schultz V;Wilder-Smith AJ;Brennan B;Pena LJ;Freitas de Oliveira França R;Linington C;Barnett SC;Willison HJ;Kohl A;Edgar JM
通讯作者：
Edgar JM