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首页> 外文期刊>Cell death and differentiation >Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis.
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Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis.

机译：展开的蛋白应答调节剂GRP78 / BiP在保护神经元凋亡中的重要作用。

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摘要

Neurodegenerative diseases are often associated with dysfunction in protein quality control. The endoplasmic reticulum (ER), a key site for protein synthesis, senses stressful conditions by activating the unfolded protein response (UPR). In this study we report the creation of a novel mouse model in which GRP78/BiP, a major ER chaperone and master regulator of UPR, is specifically eliminated in Purkinje cells (PCs). GRP78-depleted PCs activate UPR including the induction of GRP94, PDI, CHOP and GADD34, feedback suppression of eIF2alpha phosphorylation and apoptotic cell death. In contrast to current models of protein misfolding in which an abnormal accumulation of ubiquitinated protein is prominent, cytosolic ubiquitin staining is dramatically reduced in GRP78-null PCs. Ultrastructural evaluation reveals that the ER shows prominent dilatation with focal accumulation of electron-dense material within the ER. The mice show retarded growth and severe motor coordination defect by week 5 and cerebellar atrophy by week 13. Our studies uncover a novel link between GRP78 depletion and reduction in cytosolic ubiquitination and establish a novel mouse model of accelerated cerebellar degeneration with basic and clinical applications.
机译：神经退行性疾病通常与蛋白质质量控​​制功能障碍有关。内质网（ER）是蛋白质合成的关键部位，它通过激活未折叠的蛋白质反应（UPR）来感知压力状态。在这项研究中，我们报告了一种新型小鼠模型的创建，其中在Purkinje细胞（PC）中特异消除了GRP78 / BiP（一种主要的ER伴侣和UPR的主调节剂）。消耗GRP78的PC激活UPR，包括诱导GRP94，PDI，CHOP和GADD34，反馈抑制eIF2alpha磷酸化和凋亡细胞死亡。与目前普遍存在的泛素化蛋白异常积累的蛋白质错误折叠模型相反，在无GRP78的PC中，胞浆泛素染色显着减少。超微结构评估显示，ER表现出显着的扩张，并且在ER内电子致密材料的焦点积累。小鼠在第5周时显示出生长迟缓和严重的运动协调缺陷，在第13周时显示出小脑萎缩。我们的研究揭示了GRP78耗竭与胞质泛素化减少之间的新型联系，并建立了具有小脑退化的新型小鼠模型，具有基础和临床应用。

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