Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway
Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway
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在脊髓性肌萎缩中激活ATF6可通过IRE1α-XBP1通路促进SMN表达和运动神经元存活
DOI：
10.1111/nan.12816
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发表时间：
2022-03-30
影响因子：
5
通讯作者：
Charbonnier, Frederic
中科院分区：
文献类型：
--
作者：
D'Amico, Domenico;Biondi, Olivier;Charbonnier, Frederic
目的：脊髓性肌萎缩症（SMA）是一种由运动神经元（SMN）存活缺陷引起的神经肌肉疾病，可导致运动神经元（MN）变性和严重的肌肉萎缩。增加SMN的基因疗法已经证明了它们的疗效，但并非对所有患者都有效。在这里，我们探讨了SMA病理学中的未折叠蛋白反应（UPR）状态，并探讨了UPR调节是否对SMA patients.Methods有益：我们通过RT-qPCR和蛋白质印迹分析了SMA患者iPSC衍生的MN和一个SMA细胞系中关键UPR蛋白的表达和激活，其中SMN表达被重建（拯救）。我们通过使用成肌细胞和成纤维细胞SMA患者细胞和不同严重程度的SMA小鼠模型来补充这种方法。最后，我们测试了在体外和体内的影响，IRE 1 α/XBP 1通路恢复SMN的表达和随后的neuroprotection.Results：我们报告说，IRE 1 α/XBP 1分支的未折叠的蛋白质反应被破坏SMA，与消耗的XBP 1的IRE 1 α激活模式无关。SMA成纤维细胞中XBP 1 s的过表达被证明在转录上增强SMN表达。重要的是，在严重的SMA样小鼠，诱导SMN的表达和脊髓MN protection.Conclusions的再平衡XBP 1 s的表达：我们已经确定了XBP 1 s耗尽作为SMA发病机制的一个因素，这种转录因子的调制被证明是一个合理的治疗途径，在患者的药理干预的背景下。
Aim: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by survival of motor neuron (SMN) deficiency that induces motor neuron (MN) degeneration and severe muscular atrophy. Gene therapies that increase SMN have proven their efficacy but not for all patients. Here, we explored the unfolded protein response (UPR) status in SMA pathology and explored whether UPR modulation could be beneficial for SMA patients.Methods: We analysed the expression and activation of key UPR proteins by RT-qPCR and by western blots in SMA patient iPSC-derived MNs and one SMA cell line in which SMN expression was re-established (rescue). We complemented this approach by using myoblast and fibroblast SMA patient cells and SMA mouse models of varying severities. Finally, we tested in vitro and in vivo the effect of IRE1 alpha/XBP1 pathway restoration on SMN expression and subsequent neuroprotection.Results: We report that the IRE1 alpha/XBP1 branch of the unfolded protein response is disrupted in SMA, with a depletion of XBP1s irrespective of IRE1 alpha activation pattern. The overexpression of XBP1s in SMA fibroblasts proved to transcriptionally enhance SMN expression. Importantly, rebalancing XBP1s expression in severe SMA-like mice, induced SMN expression and spinal MN protection.Conclusions: We have identified XBP1s depletion as a contributing factor in SMA pathogenesis, and the modulation of this transcription factor proves to be a plausible therapeutic avenue in the context of pharmacological interventions for patients.