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Here, we identify an early stress-associated oligodendrocyte state characterized by a rapid, post-transcriptional loss of the lineage-defining transcription factor Oligodendrocyte Transcription Factor 2 (OLIG2). Using the cuprizone model of toxic demyelination, we observed an early appearance of OLIG2\n                    <jats:sup>low<\/jats:sup>\n                    expressing oligodendrocytes, followed by the emergence of OLIG2-negative oligodendrocytes at later stages. This observation was particularly pronounced among cells expressing the integrated stress response marker Activating Transcription Factor 3 (ATF3). Transcriptomic analysis, quantitative PCR, and combined in situ hybridization\u2013immunohistochemistry confirmed that these changes occurred without a corresponding reduction in\n                    <jats:italic>Olig2<\/jats:italic>\n                    mRNA levels, indicating that OLIG2 protein loss is a stress-induced, post-transcriptional event not captured by RNA-level profiling. A similar phenotype was observed in a reversible metabolic stress paradigm (i.e., chronic starvation model) and in\n                    <jats:italic>post-mortem<\/jats:italic>\n                    MS lesions, where stressed oligodendrocytes showed reduced or absent OLIG2 protein expression. Pharmacological intervention with the sphingosine-1-phosphate receptor modulator siponimod during cuprizone intoxication attenuated OLIG2 protein loss, indicating that this stress-induced state is pharmacologically modifiable. These findings reveal a transient and potentially reversible phenotype in stressed oligodendrocytes that may precede overt cell loss or demyelination. Thus, OLIG2 protein loss may serve as an early indicator of oligodendrocyte stress and a possible therapeutic target for preserving myelin integrity in demyelinating disorders. These findings have additional methodological implications as stressed oligodendrocytes may evade detection using OLIG2-based lineage markers.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03000-x","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:17:09Z","timestamp":1774372629000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of oligodendrocyte transcription factor 2 protein expression in metabolically stressed oligodendrocytes"],"prefix":"10.1007","volume":"151","author":[{"given":"Hannes","family":"Kaddatz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lukas","family":"Wenzel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emil","family":"Pril","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Meien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Harz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Burkert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Newshan","family":"Behrangi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annelie","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Frintrop","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Amor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Kipp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leo","family":"Heinig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"3000_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.cmet.2009.06.002","volume":"10","author":"SH Back","year":"2009","unstructured":"Back SH, Scheuner D, Han J, Song B, Ribick M, Wang J et al (2009) Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. 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