Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot-Marie-Tooth 1 B mice
Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot-Marie-Tooth 1 B mice
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DOI：
10.1016/j.neuron.2007.12.021
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发表时间：
2008-02-07
期刊：
影响因子：
16.2
通讯作者：
Wrabetz, Lawrence
中科院分区：
文献类型：
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作者：
Pennuto, Maria;Tinelli, Elisa;Wrabetz, Lawrence
PO糖蛋白（POS63del）中丝氨酸63的缺失导致人类Charcot-Marie-Tooth 1b神经病变，POS63del在转基因小鼠中产生类似的脱髓鞘神经病变。POS63del保留在内质网中，不能并入髓磷脂。在这里，我们报道POS63clel是错误折叠的，雪旺细胞产生相应的典型未折叠蛋白反应（UPR），包括转录因子CHOP的表达，之前与内质网应激细胞的凋亡有关。UPR激活和CHOP表达动态响应POS63del水平，并且是可逆的，但仅与雪旺细胞的有限凋亡相关。尽管如此，S63del小鼠的Chop消融完全挽救了它们的运动缺陷，并将活动性脱髓鞘减少了2倍。这表明，通过UPR CHOP臂的信号传导可引起遗传性神经病变的脱髓鞘。S63del小鼠也提供了一个机会来探索细胞如何在长时间的内质网应激下功能障碍而存活，这对与错误折叠蛋白相关的神经变性很重要。
Deletion of serine 63 from PO glycoprotein (POS63del) causes Charcot-Marie-Tooth 1 B neuropathy in humans, and POS63del produces a similar demyelinating neuropathy in transgenic mice. POS63del is retained in the endoplasmic reticulum and fails to be incorporated into myelin. Here we report that POS63clel is mis-folded and Schwann cells mount a consequential canonical unfolded protein response (UPR), including expression of the transcription factor CHOP, previously associated with apoptosis in ER-stressed cells. UPR activation and CHOP expression respond dynamically to POS63del levels and are reversible but are associated with only limited apoptosis of Schwann cells. Nonetheless, Chop ablation in S63del mice completely rescues their motor deficit and reduces active demyelination 2-fold. This indicates that signaling through the CHOP arm of the UPR provokes demyelination in inherited neuropathy. S63del mice also provide an opportunity to explore how cells can dysfunction yet survive in prolonged ER stress-important for neurodegeneration related to misfolded proteins.