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Abstract：
Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.
摘要：
髓鞘蛋白零（MPZ）的突变通常与Charcot-Marie-Tooth1B（CMT1B）疾病有关，脱髓鞘性神经病的最常见形式之一。一些MPZ突变体的发病机制，如S63del和R98C，涉及MPZ在髓鞘化雪旺细胞的内质网（ER）中的错误折叠和保留。为了应对蛋白毒性ER应激，Schwann细胞产生未折叠的蛋白质反应（UPR），其特征是激活PERK，ATF6和IRE1α/XBP1途径。先前的结果表明，靶向PERKUPR途径减轻了CMT1B小鼠模型中的神经病变；然而，其他UPR通路在疾病发病机制中的作用仍知之甚少.这里,我们探讨了IRE1α/XBP1信号在正常髓鞘形成和CMT1B中的重要性。为了应对ER压力，IRE1α被激活以刺激Xbp1mRNA的非规范剪接以产生剪接的Xbp1(Xbp1s)。这导致适应性转录因子XBP1s的表达增加，它调节涉及多种途径的基因的表达，包括ER蛋白抑制。我们生成了小鼠模型，其中Xbp1在施万细胞中被特别删除，阻止这些细胞中的XBPls激活。我们观察到Xbp1对于正常发育髓鞘形成是不必要的，损伤后的髓鞘维持和髓鞘再生。然而,Xbp1缺失显着恶化了在年轻和成年CMT1B神经病动物中观察到的骨髓增生异常以及电生理和运动参数。RNAseq分析表明，XBP1s在CMT1B小鼠模型中很大程度上通过诱导ER蛋白停滞基因发挥其适应性功能。因此，Xbp1缺陷小鼠神经病变的恶化伴随着施万细胞中ER应激途径和IRE1介导的RIDD信号传导的上调，表明通过IRE1激活XBP1在限制突变蛋白毒性中起关键作用，并且这种毒性不能通过其他应激反应来补偿。在S63del和R98C小鼠模型中，XBP1s的施万细胞特异性过表达部分重新建立了施万细胞的蛋白质停滞并减轻了CMT1B的严重程度。此外,选择性,IRE1α/XBP1信号的药理激活改善了S63del背根神经节外植体的髓鞘形成。总的来说，这些数据表明,XBP1在不同的蛋白毒性CMT1B神经病变模型中具有重要的适应性作用,提示IRE1α/XBP1通路的激活可能是CMT1B治疗的一种途径,也可能是其他以UPR激活为特征的神经病变的治疗途径.
