近日，美国国立卫生研究院教授Naoko Mizuno及其团队的研究开发出了艾泊霉素-B诱导中枢神经系统轴突再生的原位结构机制。这一研究成果于2025年11月12日发表在国际顶尖学术期刊《自然》上。

为了解决细胞内对损伤的反应，该课题组人员开发了一个原位冷冻电子断层扫描和冷冻电子显微镜平台来模拟轴突损伤，并展示了药物艾替隆B诱导丘脑轴突再生的结构机制。课题组观察到稳定的微管延伸到损伤部位之外，产生膜张力并驱动膜膨胀。低温电子显微镜以3.19Å的分辨率显示了微管的原位结构，该结构在再生前沿与微管晶格内的埃博霉素B结合。在修复过程中，微管蛋白细胞被运送到再生部位的聚合微管中。这些微管芽作为各种囊泡和内质网的支架，促进轴突修复所需材料的供应，直到膜张力恢复正常。该团队证明了神经元细胞具有意想不到的能力来适应艾泊霉素B诱导的应变，这种应变会产生稳态失衡，并激活轴突到再生模式。

研究人员表示，与外周神经系统的神经元和胚胎发育期间的神经元生长不同，成人中枢神经系统（CNS）的轴突在损伤后不会再生。阻止中枢神经系统神经元再生的分子机制在很大程度上仍然是未知的。

附：英文原文

Title: In situ structural mechanism of epothilone-B-induced CNS axon regeneration

Author: Bodakuntla, Satish, Taira, Kenichiro, Yamada, Yurika, Alvarez-Brecht, Pelayo, Cada, A. King, Basnet, Nirakar, Zhang, Rui, Martinez-Sanchez, Antonio, Biertmpfel, Christian, Mizuno, Naoko

Issue&Volume: 2025-11-12

Abstract: Axons in the adult central nervous system (CNS) do not regenerate following injury, in contrast to neurons in the peripheral nervous system and neuronal growth during embryonic development. The molecular mechanisms that prevent regeneration of neurons in the CNS remain largely unknown1,2. Here, to address the intracellular response to injury, we developed an in situ cryo-electron tomography and cryo-electron microscopy platform to mimic axonal damage and present the structural mechanism underlying thalamic axon regeneration induced by the drug epothilone B. We observed that stabilized microtubules extend beyond the injury site, generating membrane tension and driving membrane expansion. Cryo-electron microscopy reveals the in situ structure of microtubules at 3.19 resolution, which engage epothilone B within the microtubule lattice at the regenerating front. During repair, tubulin clusters are delivered and incorporated into polymerizing microtubules at the regenerating site. These microtubule shoots serve as scaffolds for various types of vesicles and endoplasmic reticulum, facilitating the supply of materials necessary for axon repair until membrane tension normalizes. We demonstrate the unexpected ability of neuronal cells to adjust to strain induced by epothilone B, which creates homeostatic imbalances and activates axons to regeneration mode.

DOI: 10.1038/s41586-025-09654-z

Source: https://www.nature.com/articles/s41586-025-09654-z