Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration.
Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration.
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DOI：
10.1016/j.ymthe.2021.01.033
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发表时间：
2021-02
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通讯作者：
René L. Vidal;Denisse Sepúlveda;Paulina Troncoso-Escudero;Paula García-Huerta;Constanza Gonzalez;L. Plate;C. Jerez;J. Cánovas;Claudia A. Rivera;Valentina Castillo;M. Cisternas;Sirley Leal;Alexis Martínez;Julia M. Grandjean;Donzelli Sonia;H. Lashuel;Alberto J. M. Martin;Verónica Latapiat;S. Matus;S. Sardi;R. Wiseman;C. Hetz
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作者：
René L. Vidal;Denisse Sepúlveda;Paulina Troncoso-Escudero;Paula García-Huerta;Constanza Gonzalez;L. Plate;C. Jerez;J. Cánovas;Claudia A. Rivera;Valentina Castillo;M. Cisternas;Sirley Leal;Alexis Martínez;Julia M. Grandjean;Donzelli Sonia;H. Lashuel;Alberto J. M. Martin;Verónica Latapiat;S. Matus;S. Sardi;R. Wiseman;C. Hetz
内质网(ER)蛋白稳定性的改变在多种与蛋白质聚集异常相关的神经退行性疾病中观察到。未折叠蛋白反应(UPR)的激活使适应性反应能够恢复ER蛋白平衡和细胞功能。UPR是由特殊的压力传感器启动的，这些传感器通过转录因子ATF4、ATF6f和XBP1s的协同作用参与基因表达程序。尽管UPR信号通常被研究为独特的线性信号分支，但相关证据表明，ATF6f和XBP1s可能在物理上相互作用，调节UPR靶基因的一个子集。在这项研究中，我们设计了一种名为UPRplus的ATF6f/XBP1S融合蛋白，就其选择性转录活性而言，它具有异源二聚体的作用。基于细胞的研究表明，UPRplus在减少突变的亨廷顿蛋白和α-突触核蛋白的异常聚集方面比单独使用XBP1或ATF6有更强的效果。我们开发了一种使用腺相关病毒(AAV)将UPRplus转移到大脑的基因转移方法，并在帕金森病和亨廷顿病的临床前模型中展示了有效的神经保护作用。这些结果支持这样的概念，即将UPR介导的基因表达导向特定的适应程序可能是一种可能的策略，以优化该途径在不同疾病条件下的有益效果。
Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotectionin vivoin preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.