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PromISR-6, a Guanabenz Analogue, Improves Cellular Survival in an Experimental Model of Huntington's Disease.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2019-07-30 , DOI: 10.1021/acschemneuro.9b00185 Jeyapriya Rajameenakshi Sundaram 1 , Yilong Wu , Irene Chengjie Lee , Simi Elizabeth George , Monalisa Hota , Sujoy Ghosh , Sashi Kesavapany 2 , Mahmood Ahmed 2 , Eng-King Tan 1 , Shirish Shenolikar
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2019-07-30 , DOI: 10.1021/acschemneuro.9b00185 Jeyapriya Rajameenakshi Sundaram 1 , Yilong Wu , Irene Chengjie Lee , Simi Elizabeth George , Monalisa Hota , Sujoy Ghosh , Sashi Kesavapany 2 , Mahmood Ahmed 2 , Eng-King Tan 1 , Shirish Shenolikar
Affiliation
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Guanabenz (GBZ), an α2-adrenergic agonist, demonstrated off-target effects that restored protein homeostasis and ameliorated pathobiology in experimental models of neurodegenerative disease. However, GBZ did not directly activate the integrated stress response (ISR), and its proposed mode of action remains controversial. Utilizing an iterative in silico screen of over 10,000 GBZ analogues, we analyzed 432 representative compounds for cytotoxicity in Wild-type, PPP1R15A-/-, and PPP1R15B-/- mouse embryonic fibroblasts. Nine compounds clustering into three functional groups were studied in detail using cell biological and biochemical assays. Our studies demonstrated that PromISR-6 is a potent GBZ analogue that selectively activated ISR, eliciting sustained eIF2α phosphorylation. ISRIB, an ISR inhibitor, counteracted PromISR-6-mediated translational inhibition and reduction in intracellular mutant Huntingtin aggregates. Reduced protein synthesis combined with PromISR-6-stimulated autophagic clearance made PromISR-6 the most efficacious GBZ analogue to reduce Huntingtin aggregates and promote survival in a cellular model of Huntington's disease.
中文翻译：
PromISR-6是一种瓜纳本斯的类似物，可以在亨廷顿氏病实验模型中提高细胞存活率。
瓜纳本斯（GBZ）是一种α2肾上腺素能激动剂，在神经退行性疾病的实验模型中显示出脱靶效应，可恢复蛋白质稳态并改善病理生物学。但是，GBZ并未直接激活综合应激反应（ISR），其拟议的作用方式仍存在争议。利用超过10,000 GBZ类似物的迭代计算机模拟筛选，我们分析了432种代表性化合物在野生型，PPP1R15A-/-和PPP1R15B-/-小鼠胚胎成纤维细胞中的细胞毒性。使用细胞生物学和生化分析详细研究了聚类为三个官能团的九种化合物。我们的研究表明，PromISR-6是有效的GBZ类似物，可选择性激活ISR，引起持续的eIF2α磷酸化。ISRIB，ISR抑制剂，抵消了PromISR-6介导的翻译抑制和细胞内突变型Huntingtin聚集体的减少。减少的蛋白质合成，再加上PromISR-6刺激的自噬清除，使PromISR-6成为最有效的GBZ类似物，可减少Huntingtin聚集并促进亨廷顿氏病细胞模型的存活。
更新日期：2019-07-17
中文翻译：
PromISR-6是一种瓜纳本斯的类似物，可以在亨廷顿氏病实验模型中提高细胞存活率。
瓜纳本斯（GBZ）是一种α2肾上腺素能激动剂，在神经退行性疾病的实验模型中显示出脱靶效应，可恢复蛋白质稳态并改善病理生物学。但是，GBZ并未直接激活综合应激反应（ISR），其拟议的作用方式仍存在争议。利用超过10,000 GBZ类似物的迭代计算机模拟筛选，我们分析了432种代表性化合物在野生型，PPP1R15A-/-和PPP1R15B-/-小鼠胚胎成纤维细胞中的细胞毒性。使用细胞生物学和生化分析详细研究了聚类为三个官能团的九种化合物。我们的研究表明，PromISR-6是有效的GBZ类似物，可选择性激活ISR，引起持续的eIF2α磷酸化。ISRIB，ISR抑制剂，抵消了PromISR-6介导的翻译抑制和细胞内突变型Huntingtin聚集体的减少。减少的蛋白质合成，再加上PromISR-6刺激的自噬清除，使PromISR-6成为最有效的GBZ类似物，可减少Huntingtin聚集并促进亨廷顿氏病细胞模型的存活。
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