{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:18:04Z","timestamp":1790162284671,"version":"4.1.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Acute ischemic stroke initiates a rapid convergence of excitotoxicity, calcium overload, oxidative stress, neuroinflammation, and energetic failure. Although reperfusion therapies remain central to acute care, they do not directly address the structural failure of injured neuronal networks. This narrative review examines the neuronal microtubule cytoskeleton as an active regulatory platform whose function is governed by the tubulin code: tubulin isotype composition and post-translational modifications. The review integrates evidence that ischemia alters alpha-tubulin K40 acetylation, detyrosination, delta-2 tubulin accumulation, and polyglutamylation, while also examining emerging roles for palmitoylation, lactylation, and glycylation-related PTM cross-talk. Particular emphasis is placed on the HDAC6-alpha-tubulin acetylation axis, MIF-AIF parthanatos signaling, vasohibin-dependent detyrosination, CCP1-dependent control of polyglutamylation, TUBA4A-GSK3beta-Tau scaffolding, beta-tubulin isotype effects on whole-lattice behavior, and lactylation-mediated repair. Together, these pathways support a phase-specific model in which early cytoprotection preserves transport-competent microtubules, whereas later recovery requires adaptive cytoskeletal remodeling and neuroplasticity.<\/jats:p>","DOI":"10.3389\/fnins.2026.1971973","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:57:11Z","timestamp":1790161031000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The tubulin code in acute ischemic stroke: post-translational reprogramming of the neuronal cytoskeleton and implications for phase-specific neuroprotection"],"prefix":"10.3389","volume":"20","author":[{"given":"David","family":"Bar-Or","sequence":"first","affiliation":[{"name":"Stroke Research Department, Swedish Medical Center","place":["Englewood, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Thomas","sequence":"additional","affiliation":[{"name":"Stroke Research Department, Swedish Medical Center","place":["Englewood, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Schroder","sequence":"additional","affiliation":[{"name":"Knoebel Institute of Healthy Aging, University of Denver","place":["Denver, CO, United States"]},{"name":"Department of Chemistry and Biochemistry, University of Denver","place":["Denver, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Burrell","sequence":"additional","affiliation":[{"name":"Neurology Department, Swedish Medical Center","place":["Englewood, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"Groechel","sequence":"additional","affiliation":[{"name":"Stroke Research Department, Swedish Medical Center","place":["Englewood, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Paredes","sequence":"additional","affiliation":[{"name":"Knoebel Institute of Healthy Aging, University of Denver","place":["Denver, CO, United States"]},{"name":"Department of Electrical and Computer Engineering, University of Denver","place":["Denver, CO, United States"]},{"name":"Department of Neurology, Johns Hopkins School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2384","DOI":"10.1007\/s13311-021-01142-2","article-title":"Chemotherapy-induced peripheral neuropathy: mechanisms and therapeutic avenues","volume":"18","author":"Bae","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1021\/acschemneuro.8b00497","article-title":"Power of tyrosine assembly in microtubule stabilization and neuroprotection fueled by phenol appendages","volume":"10","author":"Barman","year":"2019","journal-title":"ACS Chem. 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Rep."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"19626","DOI":"10.1038\/srep19626","article-title":"Tubastatin a, an HDAC6 inhibitor, alleviates stroke-induced brain infarction and functional deficits","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1784112","DOI":"10.3389\/fimmu.2026.1784112","article-title":"Lactylation at the crossroads of metabolism and epigenetics in neuroinflammation","volume":"17","author":"Wang","year":"2026","journal-title":"Front. Immunol."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1759658","DOI":"10.3389\/fimmu.2026.1759658","article-title":"From microtubule remodeling to clinical translation: the multifaceted roles of vasohibin-1 in disease modulation","volume":"17","author":"Wei","year":"2026","journal-title":"Front. Immunol."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1016\/j.devcel.2009.04.008","article-title":"TTLL3 is a tubulin glycine ligase that regulates the assembly of cilia","volume":"16","author":"Wloga","year":"2009","journal-title":"Dev. Cell"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.jchemneu.2019.03.002","article-title":"The effects of epothilone D on microtubule degradation and delayed neuronal death in the hippocampus following transient global ischemia","volume":"98","author":"Xiong","year":"2019","journal-title":"J. Chem. Neuroanat."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"e007626","DOI":"10.1161\/JAHA.117.007626","article-title":"Epothilone B benefits nigrostriatal pathway recovery by promoting microtubule stabilization after intracerebral hemorrhage","volume":"7","author":"Yang","year":"2018","journal-title":"J. Am. 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