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We examined acute (&lt;48\u2009h post\u2010SCI) and chronic (6\u2009weeks post\u2010SCI) effects of conditionally deleting <jats:italic>Perk<\/jats:italic> from OLs prior to SCI. While <jats:italic>Perk<\/jats:italic> transcript is expressed in many types of cells in the adult spinal cord, its levels are disproportionately high in OL lineage cells. Deletion of OL\u2010<jats:italic>Perk<\/jats:italic> prior to SCI resulted in: (1) enhanced acute phosphorylation of eIF2\u03b1, a major PERK substrate and the critical mediator of the integrated stress response (ISR), (2) enhanced acute expression of the downstream ISR genes <jats:italic>Atf4<\/jats:italic>, <jats:italic>Ddit3\/Chop<\/jats:italic>, and <jats:italic>Tnfrsf10b<\/jats:italic>\/<jats:italic>Dr5<\/jats:italic>, (3) reduced acute OL lineage\u2010specific <jats:italic>Olig2<\/jats:italic> mRNA, but not neuronal or astrocytic mRNAs, (4) chronically decreased OL content in the spared white matter at the injury epicenter, (5) impaired hindlimb locomotor recovery, and (6) reduced chronic epicenter white matter sparing. Cultured primary OL precursor cells with reduced PERK expression and activated ER stress response showed: (1) unaffected phosphorylation of eIF2\u03b1, (2) enhanced ISR gene induction, and (3) increased cytotoxicity. Therefore, OL\u2010<jats:italic>Perk<\/jats:italic> deficiency exacerbates ISR signaling and potentiates white matter damage after SCI. The latter effect is likely mediated by increased loss of <jats:italic>Perk<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> OLs.<\/jats:p>","DOI":"10.1002\/glia.24525","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T10:34:07Z","timestamp":1712572447000},"page":"1259-1272","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Oligodendrocyte\u2010selective deletion of the <scp>eIF2\u03b1<\/scp> kinase <i>Perk\/Eif2ak3<\/i> limits functional recovery after spinal cord injury"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4161-2516","authenticated-orcid":false,"given":"Sujata","family":"Saraswat Ohri","sequence":"first","affiliation":[{"name":"Kentucky Spinal Cord Injury Research Center  Louisville Kentucky USA"},{"name":"Department of Neurological Surgery University of Louisville School of Medicine  Louisville 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