Attenuating the Endoplasmic Reticulum Stress Response Improves Functional Recovery After Spinal Cord Injury
Attenuating the Endoplasmic Reticulum Stress Response Improves Functional Recovery After Spinal Cord Injury
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DOI：
10.1002/glia.21191
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发表时间：
2011-10-01
期刊：
影响因子：
6.2
通讯作者：
Whittemore, Scott R.
中科院分区：
文献类型：
--
作者：
Ohri, Sujata Saraswat;Maddie, Melissa A.;Whittemore, Scott R.
未折叠蛋白反应（UPR）的激活参与了许多CNS髓鞘异常的发病机制;然而，其在创伤性脊髓损伤（SCI）诱导的脱髓鞘中的直接作用尚不清楚。UPR是一种进化上保守的细胞防御机制，启动以恢复内质网稳态，以响应各种细胞应激，包括感染，创伤和氧化损伤。然而，如果未得到补偿，UPR触发凋亡性细胞死亡。我们证明了UPR的三个信号分支，包括PERK，ATF 6和IRE 1 α，在小鼠挫伤性SCI模型中迅速启动，特别是在损伤中心。各种UPR标记物的免疫组织化学分析显示，在神经元中，UPR出现在6和24小时后SCI。相反，在少突胶质细胞和星形胶质细胞中，UPR至少持续到SCI后3天。UPR相关的促凋亡转录调节因子CHOP是UPR标记物中上调的神经元和少突胶质细胞，但不是在星形胶质细胞，创伤小鼠脊髓。为了直接分析其在SCI中的作用，WT和CHOP缺失小鼠接受中度T9挫伤性损伤。CHOP的缺失导致挫伤性SCI后UPR的整体衰减。此外，后肢运动的分析表明，与WT动物相比，CHOP基因敲除小鼠的白质保留、髓鞘碱性蛋白和Claudin 11的转录水平增加以及少突胶质细胞凋亡减少相关的显著功能恢复。因此，我们的研究提供了证据表明，UPR有助于创伤性SCI后少突胶质细胞的损失。(C)2011 Wiley-Liss，Inc.
Activation of the unfolded protein response (UPR) is involved in the pathogenesis of numerous CNS myelin abnormalities; yet, its direct role in traumatic spinal cord injury (SCI)-induced demyelination is not known. The UPR is an evolutionarily conserved cell defense mechanism initiated to restore endoplasmic reticulum homeostasis in response to various cellular stresses including infection, trauma, and oxidative damage. However, if uncompensated, the UPR triggers apoptotic cell death. We demonstrate that the three signaling branches of UPR including the PERK, ATF6, and IRE1 alpha are rapidly initiated in a mouse model of contusive SCI specifically at the injury epicenter. Immunohistochemical analyses of the various UPR markers revealed that in neurons, the UPR appeared at 6 and 24-h post-SCI. In contrast, in oligodendrocytes and astroglia, UPR persisted at least for up to 3 days post-SCI. The UPR-associated proapoptotic transcriptional regulator CHOP was among the UPR markers upregulated in neurons and oligodendrocytes, but not in astrocytes, of traumatized mouse spinal cords. To directly analyze its role in SCI, WT and CHOP null mice received a moderate T9 contusive injury. Deletion of CHOP led to an overall attenuation of the UPR after contusive SCI. Furthermore, analyses of hindlimb locomotion demonstrated a significant functional recovery that correlated with an increase in white-matter sparing, transcript levels of myelin basic protein, and Claudin 11 and decreased oligodendrocyte apoptosis in CHOP null mice in contrast to WT animals. Thus, our study provides evidence that the UPR contributes to oligodendrocyte loss after traumatic SCI. (C) 2011 Wiley-Liss, Inc.