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

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dc.contributor.authorNaoko Mizuno
dc.contributor.authorBodakuntla, Satish
dc.contributor.authorTaira, Kenichiro
dc.contributor.authorYamada, Yurika
dc.contributor.authorAlvarez Brecht, Pelayo
dc.contributor.authorCada, A. King
dc.contributor.authorBasnet, Nirakar
dc.contributor.authorZhang, Rui
dc.contributor.authorMartínez Sáchez, Antonio
dc.contributor.authorBiertümpfel, Christian
dc.contributor.authorMizuno, Naoko
dc.contributor.departmentIngeniería de la Información y las Comunicaciones
dc.date.accessioned2026-01-16T08:29:32Z
dc.date.available2026-01-16T08:29:32Z
dc.date.copyright© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025, modified publication 2026
dc.date.issued2025-11-12
dc.description.abstractAxons 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 cryoelectron 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 Å 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.
dc.formatapplication/pdf
dc.format.extent35
dc.identifier.citationNature, 2025, Vol. 648, pp. 477–487
dc.identifier.doihttps://doi.org/10.1038/s41586-025-09654-z
dc.identifier.urihttp://hdl.handle.net/10201/187649
dc.languageeng
dc.publisherNature Research
dc.relationThis work used the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), Division of Intramural Research Program of the National Heart, Lung and Blood Institute (1ZIAHL006264) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH. The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the US Department of Health and Human Services. S.B. and A.K.C. are supported by the Lenfant fellowship. K.T. is a recipient of Uehara memorial fellowship and Y.Y. is a recipient of a Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. The authors declare no competing interests.
dc.relation.publisherversionhttps://www.nature.com/articles/s41586-025-09654-z
dc.rightsAttribution- 4.0 International*
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by4.0/*
dc.subject.odsObjetivo 3: Salud
dc.titleIn situ structural mechanism of epothilone-B-induced CNS axon regeneration
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublicationes
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