Gobrecht Philipp, Andreadaki Anastasia, Diekmann Heike, Heskamp Annemarie, Leibinger Marco, Fischer Dietmar
Division of Experimental Neurology, Department of Neurology, Medical Faculty, Heinrich Heine University of Düsseldorf, 40225 Düsseldorf, Germany.
Division of Experimental Neurology, Department of Neurology, Medical Faculty, Heinrich Heine University of Düsseldorf, 40225 Düsseldorf, Germany
J Neurosci. 2016 Apr 6;36(14):3890-902. doi: 10.1523/JNEUROSCI.4486-15.2016.
Functional recovery of injured peripheral neurons often remains incomplete, but the clinical outcome can be improved by increasing the axonal growth rate. Adult transgenic GSK3α(S/A)/β(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 vitroandin vivoanalysis of GSK3 single knock-in mice revealed the unexpected contribution of GSK3α in addition to GSK3β, 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 GSK3α(S/A)/β(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 acceleratedin vivoaxon regeneration and functional recovery similar to GSK3α(S/A)/β(S/A) mice. Thus, reducing microtubule detyrosination in axonal tips may be a novel, clinically suitable strategy to treat nerve damage.
Peripheral nerve regeneration often remains incomplete, due to an insufficient growth rate of injured axons. Transgenic mice with sustained GSK3 activity showed markedly accelerated nerve regeneration upon injury. Here, we identified the molecular mechanism underlying this phenomenon and provide a novel therapeutic principle for promoting nerve repair. Analysis of transgenic mice revealed a dependence on overall GSK3 activity and reduction of microtubule detyrosination in axonal tips. Pharmacological inhibition of detyrosination by parthenolide fully mimicked this axon growth promotion in wild-type mice. Strikingly, local or systemic treatment with parthenolidein vivomarkedly accelerated axon regeneration and functional recovery. Thus, pharmacological inhibition of microtubule detyrosination may be a novel, clinically suitable strategy for nerve repair with potential relevance for human patients.
受损外周神经元的功能恢复往往仍不完整，但通过提高轴突生长速度可改善临床结果。具有持续GSK3活性的成年转基因GSK3α(S/A)/β(S/A)敲入小鼠表现出坐骨神经再生明显加速。在此，我们揭示了这一现象背后的分子机制，从而产生了一种促进神经损伤后功能恢复的新药理学方法。对GSK3单敲入小鼠的体外和体内分析揭示了除GSK3β外GSK3α的意外作用，因为两种GSK3(S/A)敲入均改善了轴突再生。此外，生长刺激取决于总体GSK3活性，与微管相关蛋白1B磷酸化增加及轴突末端微管去酪氨酸化减少相关。小白菊内酯或菊苣酸对去酪氨酸化的药理学抑制在野生型动物中模拟了这种轴突生长促进作用，尽管在GSK3α(S/A)/β(S/A)小鼠中无效。这些结果支持以下结论：持续的GSK3活性主要作用于生长轴突中的微管，使其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小白菊内酯的作用。令人惊讶的是，在野生型小鼠中局部或全身应用小白菊内酯剂量依赖性地加速了体内轴突再生和功能恢复，类似于GSK3α(S/A)/β(S/A)小鼠。因此，减少轴突末端微管去酪氨酸化可能是一种治疗神经损伤的新的、临床适用的策略。
由于受损轴突生长速度不足，外周神经再生往往仍不完整。具有持续GSK3活性的转基因小鼠在受伤后表现出明显加速的神经再生。在此，我们确定了这一现象背后的分子机制，并为促进神经修复提供了一种新的治疗原则。对转基因小鼠的分析揭示了对总体GSK3活性的依赖性以及轴突末端微管去酪氨酸化的减少。小白菊内酯对去酪氨酸化的药理学抑制在野生型小鼠中完全模拟了这种轴突生长促进作用。令人惊讶的是，在体内用小白菊内酯进行局部或全身治疗显著加速了轴突再生和功能恢复。因此，微管去酪氨酸化的药理学抑制可能是一种新的、临床适用的神经修复策略，对人类患者可能具有相关性。
