SRC family kinase inhibitors antagonize the toxicity of multiple serotypes of botulinum neurotoxin in human embryonic stem cell-derived motor neurons.
SRC family kinase inhibitors antagonize the toxicity of multiple serotypes of botulinum neurotoxin in human embryonic stem cell-derived motor neurons.
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DOI：
10.1007/s12640-015-9526-z
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发表时间：
2015-05
影响因子：
3.7
通讯作者：
Bavari, Sina
中科院分区：
文献类型：
--
作者：
Kiris, Erkan;Burnett, James C.;Nuss, Jonathan E.;Wanner, Laura M.;Peyser, Brian D.;Du, Hao T.;Gomba, Glenn Y.;Kota, Krishna P.;Panchal, Rekha G.;Gussio, Rick;Kane, Christopher D.;Tessarollo, Lino;Bavari, Sina
关键词：
肉毒杆菌神经毒素 (BoNT) 是肉毒杆菌中毒的病原体，是运动神经元释放神经递质的有效抑制剂。目前尚无药物可以在出现疾病症状后治疗 BoNT 中毒。在这项研究中，我们探讨了关键宿主途径的调节如何影响人类运动神经元中 BoNT 中毒的过程，重点关注 Src 家族激酶 (SFK) 信号传导。来自人类胚胎干 (hES) 细胞的运动神经元经过一组 SFK 抑制剂处理，并被 A、B 或 E 型 BoNT 血清型（95% 以上的人类肉毒杆菌中毒病例由这些血清型引起）中毒。随后发现bosutinib、dasatinib、KX2-391、PP1、PP2、Src抑制剂-1和SU6656均显着拮抗所有三种血清型。此外，数据表明，用多种 SFK 抑制剂治疗 hES 来源的运动神经元可协同增加拮抗作用。从机制上讲，这些小分子似乎是通过靶向中毒所需的宿主途径来抑制 BoNT，而不是直接抑制毒素的蛋白水解活性。重要的是，所确定的抑制剂都经过了充分研究，其中一些处于临床试验阶段，而另一些则是 FDA 批准的药物。总的来说，这项研究强调了针对宿主神经元通路而不是毒素的酶成分来拮抗运动神经元中多种 BoNT 血清型的重要性。
Botulinum neurotoxins (BoNTs), the causative agents of botulism, are potent inhibitors of neurotransmitter release from motor neurons. There are currently no drugs to treat BoNT intoxication after the onset of the disease symptoms. In this study, we explored how modulation of key host pathways affects the process of BoNT intoxication in human motor neurons, focusing on Src family kinase (SFK) signaling. Motor neurons derived from human embryonic stem (hES) cells were treated with a panel of SFK inhibitors and intoxicated with BoNT serotypes A, B, or E (which are responsible for >95 % of human botulism cases). Subsequently, it was found that bosutinib, dasatinib, KX2-391, PP1, PP2, Src inhibitor-1, and SU6656 significantly antagonized all three of the serotypes. Furthermore, the data indicated that the treatment of hES-derived motor neurons with multiple SFK inhibitors increased the antagonistic effect synergistically. Mechanistically, the small molecules appear to inhibit BoNTs by targeting host pathways necessary for intoxication and not by directly inhibiting the toxins’ proteolytic activity. Importantly, the identified inhibitors are all well-studied with some in clinical trials while others are FDA-approved drugs. Overall, this study emphasizes the importance of targeting host neuronal pathways, rather than the toxin’s enzymatic components, to antagonize multiple BoNT serotypes in motor neurons.
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影响因子：
56.9
作者：
Dong, M;Yeh, F;Chapman, ER
通讯作者：
Chapman, ER
影响因子：
2.9
作者：
Fu, Zhuji;Chen, Chen;Barbieri, Joseph T.;Kim, Jung-Ja P.;Baldwin, Michael R.
通讯作者：
Baldwin, Michael R.
影响因子：
11.4
作者：
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影响因子：
4.2
作者：
Chen S
通讯作者：
Chen S
影响因子：
2.9
作者：
Blanes-Mira, C;Ibañez, C;Ferrer-Montiel, A
通讯作者：
Ferrer-Montiel, A