Oligodendrocyte-specific deletion of Xbp1 exacerbates the endoplasmic reticulum stress response and restricts locomotor recovery after thoracic spinal cord injury.
Oligodendrocyte-specific deletion of Xbp1 exacerbates the endoplasmic reticulum stress response and restricts locomotor recovery after thoracic spinal cord injury.
复制标题
少突胶质细胞特异性Xbp1缺失加剧内质网应激反应并限制胸脊髓损伤后运动恢复
DOI：
10.1002/glia.23907
复制
发表时间：
2021-03
期刊：
影响因子：
6.2
通讯作者：
Whittemore SR
中科院分区：
文献类型：
--
作者：
Saraswat Ohri S;Howard RM;Liu Y;Andres KR;Shepard CT;Hetman M;Whittemore SR
内质网应激反应（ERSR）在各种神经退行性疾病和/或CNS创伤性损伤后被激活。ERSR由三个主要臂组成，PERK，IRE-1和ATF 6，后两个有助于未折叠蛋白反应（UPR）。PERK活性与整合的应激反应（ISR）激酶PKR、HRI和GCN 2重叠，它们都通过eIF 2 α、ATF 4和CHOP进行信号传导。所有这些最初都试图恢复ER稳态，但如果ER应激未得到解决，则启动ATF 4/CHOP介导的细胞死亡。在此，我们研究肌醇需要蛋白1α（IRE 1 α）-X-box结合蛋白1（XBP 1）介导的UPR信号通路在SCI发病机制中的作用。我们证明，Xbp 1的缺失导致在培养的小鼠少突胶质细胞（OL）祖细胞（mOPCs）中ATF 4/CHOP信号转导加剧，并增强其对ER应激的敏感性。Xbp 1通路抑制剂丰卡霉素也观察到类似的效果。此外，OL谱系特异性Xbp 1丢失导致在T9水平经历中度挫伤性SCI的小鼠中ISR增强。一致的是，损伤后恢复后肢运动和白色物质保留在OL Xbp 1缺陷小鼠中减少，这与损伤中心的OPCs和OL的慢性相对密度相关。我们的结论是，IRE 1-XBP 1介导的UPR信号通路有助于恢复雌激素受体的稳态在OLs和增强白色物质的保留和功能恢复后SCI是必要的。
The endoplasmic reticulum stress response (ERSR) is activated in various neurodegenerative diseases and/or after CNS traumatic injuries. The ERSR is comprised of three major arms, PERK, IRE-1, and ATF6, with the latter two contributing to the unfolded protein response (UPR). PERK activity overlaps with the integrated stress response (ISR) kinases, PKR, HRI and GCN2 which all signal through, eIF2α, ATF4 and CHOP. All initially attempt to restore ER homeostasis, but if ER stress is unresolved, ATF4/CHOP-mediated cell death is initiated. Here, we investigate the contribution of the inositol-requiring protein-1α (IRE1α)-X-box binding protein-1 (XBP1)-mediated UPR signaling pathway to the pathogenesis of SCI. We demonstrate that deletion of Xbp1 caused an exacerbated ATF4/CHOP signaling in cultured mouse oligodendrocyte (OL) progenitor cells (mOPCs) and enhanced their sensitivity to ER stress. Similar effects were also observed with the Xbp1 pathway inhibitor toyocamycin. Furthermore, OL lineage-specific loss of Xbp1 resulted in enhanced ISR in mice that underwent moderate contusive SCI at the T9 level. Consistently, post-injury recovery of hindlimb locomotion and white matter sparing were reduced in OL Xbp1-deficient mice, that correlated with chronically relative density of OPCs and OLs at the injury epicenter. We conclude that the IRE1-XBP1-mediated UPR signaling pathway contributes to restoration of ER homeostasis in OLs and is necessary for enhanced white matter sparing and functional recovery post-SCI.
登录
查看更多内容
影响因子：
25
作者：
Lin, Wensheng;Popko, Brian
通讯作者：
Popko, Brian
影响因子：
3.5
作者：
Fuss, B;Afshari, FS;Macklin, WB
通讯作者：
Macklin, WB
影响因子：
5.3
作者：
Loy, DN;Magnuson, DSK;Whittemore, SR
通讯作者：
Whittemore, SR
影响因子：
1.5
作者：
Doerflinger, NH;Macklin, WB;Popko, B
通讯作者：
Popko, B
DOI：
10.1083/jcb.153.5.1011
发表时间：
2001-05-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Novoa I;Zeng H;Harding HP;Ron D
通讯作者：
Ron D