Promotion of Functional Nerve Regeneration by Inhibition of Microtubule Detyrosination
Promotion of Functional Nerve Regeneration by Inhibition of Microtubule Detyrosination
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DOI：
10.1523/jneurosci.4486-15.2016
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发表时间：
2016-04-06
影响因子：
5.3
通讯作者：
Fischer, Dietmar
中科院分区：
文献类型：
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作者：
Gobrecht, Philipp;Andreadaki, Anastasia;Fischer, Dietmar
受损的外周神经元的功能恢复通常仍然不完全，但临床结果可以通过增加轴突生长速率来改善。具有持续GSK 3活性的成年转基因GSK 3 α（S/A）/β（S/A）敲入小鼠显示出明显加速的坐骨神经再生。在这里，我们揭示了这种现象背后的分子机制，这导致了一种新的药理学方法，用于促进神经损伤后的功能恢复。对GSK 3单敲入小鼠的体外和体内分析揭示了除GSK 3 β外，GSK 3 α的意想不到的贡献，因为两种GSK 3（S/A）敲入均改善了轴突再生。此外，生长刺激依赖于总的GSK 3活性，与微管相关蛋白1B的磷酸化增加和轴突尖端微管脱酪氨酸减少相关。通过孤雌菊或cnicin对去酪氨酸的药理学抑制在野生型动物中模拟了这种轴突生长促进，尽管它在GSK 3 α（S/A）/β（S/A）小鼠中没有作用。这些结果支持了这样的结论，即持续的GSK 3活性主要针对生长轴突中的微管，使它们保持在更动态的状态以促进生长。因此，使用紫杉醇或诺考达唑进一步操纵微管稳定性会损害孤雌激素的作用。引人注目的是，在野生型小鼠中局部或全身应用孤雌菊糖剂量依赖性地加速体内轴突再生和功能恢复，类似于GSK 3 α（S/A）/β（S/A）小鼠。因此，减少轴突尖端微管脱酪氨酸可能是一种新的，临床上合适的治疗神经损伤的策略。
Functional recovery of injured peripheral neurons often remains incomplete, but the clinical outcome can be improved by increasing the axonal growth rate. Adult transgenic GSK3 alpha(S/A)/beta(S/A) knock-in mice with sustained GSK3 activity show markedly accelerated sciatic nerve regeneration. Here, we unraveled the molecular mechanism underlying this phenomenon, which led to a novel pharmacological approach for the promotion of functional recovery after nerve injury. In vitro and in vivo analysis of GSK3 single knock-in mice revealed the unexpected contribution of GSK3 alpha in addition to GSK3 beta, as both GSK3(S/A) knock-ins improved axon regeneration. Moreover, growth stimulation depended on overall GSK3 activity, correlating with increased phosphorylation of microtubule-associated protein 1B and reduced microtubule detyrosination in axonal tips. Pharmacological inhibition of detyrosination by parthenolide or cnicin mimicked this axon growth promotion in wild-type animals, although it had no effect in GSK3 alpha(S/A)/beta(S/A) mice. These results support the conclusion that sustained GSK3 activity primarily targets microtubules in growing axons, maintaining them in a more dynamic state to facilitate growth. Accordingly, further manipulation of microtubule stability using either paclitaxel or nocodazole compromised the effects of parthenolide. Strikingly, either local or systemic application of parthenolide in wild-type mice dose-dependently accelerated in vivo axon regeneration and functional recovery similar to GSK3 alpha(S/A)/beta(S/A) mice. Thus, reducing microtubule detyrosination in axonal tips may be a novel, clinically suitable strategy to treat nerve damage.