After spinal cord injury (SCI), re‐establishing cellular homeostasis is critical to optimize functional recovery. Central to that response is PERK signaling, which ultimately initiates a pro‐apoptotic response if cellular homeostasis cannot be restored. Oligodendrocyte (OL) loss and white matter damage drive functional consequences and determine recovery potential after thoracic contusive SCI. We examined acute (<48 h post‐SCI) and chronic (6 weeks post‐SCI) effects of conditionally deleting Perk from OLs prior to SCI. While Perk 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‐Perk prior to SCI resulted in: (1) enhanced acute phosphorylation of eIF2α, a major PERK substrate and the critical mediator of the integrated stress response (ISR), (2) enhanced acute expression of the downstream ISR genes Atf4, Ddit3/Chop, and Tnfrsf10b/Dr5, (3) reduced acute OL lineage‐specific Olig2 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 eIF2α, (2) enhanced ISR gene induction, and (3) increased cytotoxicity. Therefore, OL‐Perk deficiency exacerbates ISR signaling and potentiates white matter damage after SCI. The latter effect is likely mediated by increased loss of Perk−/− OLs.

中文翻译：

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少突胶质细胞选择性删除 eIF2α 激酶 Perk/Eif2ak3 限制脊髓损伤后的功能恢复

脊髓损伤（SCI）后，重建细胞稳态对于优化功能恢复至关重要。该反应的核心是 PERK 信号传导，如果细胞稳态无法恢复，该信号最终会启动促凋亡反应。少突胶质细胞 (OL) 损失和白质损伤会导致功能后果，并决定胸部挫伤性 SCI 后的恢复潜力。我们检查了条件删除的急性（SCI 后 <48 小时）和慢性（SCI 后 6 周）影响珀克来自 SCI 之前的 OL。尽管珀克转录本在成人脊髓的许多类型细胞中表达，其水平在 OL 谱系细胞中不成比例地高。删除 OL-珀克SCI 之前导致：(1) eIF2α 的急性磷酸化增强，eIF2α 是 PERK 的主要底物和综合应激反应 (ISR) 的关键介质，(2) 下游 ISR 基因的急性表达增强阿特夫4,Ddit3/印章， 和TNFRsf10b/博士5, (3) 减少急性 OL 谱系特异性寡核苷酸2mRNA，但不是神经元或星形细胞 mRNA，(4) 损伤中心处幸存的白质中的 OL 含量长期降低，(5) 后肢运动恢复受损，以及 (6) 慢性中心白质保留减少。 PERK 表达降低和 ER 应激反应激活的培养原代 OL 前体细胞显示：(1) eIF2α 磷酸化不受影响，(2) ISR 基因诱导增强，(3) 细胞毒性增加。因此，OL-珀克缺乏会加剧 ISR 信号传导并加剧 SCI 后的白质损伤。后一种效应可能是通过增加损失来介导的珀克−/−OL们。