Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder with currently no cure. Central to the cellular dysfunction associated with this fatal proteinopathy is the accumulation of unfolded/misfolded superoxide dismutase 1 (SOD1) in various subcellular locations. The molecular mechanism driving the formation of SOD1 aggregates is not fully understood but numerous studies suggest that aberrant aggregation escalates with folding instability of mutant apoSOD1. Recent advances on combining organelle-targeting therapies with the anti-aggregation capacity of chemical chaperones have successfully reduce the subcellular load of misfolded/aggregated SOD1 as well as their downstream anomalous cellular processes at low concentrations (micromolar range). Nevertheless, if such local aggregate reduction directly correlates with increased folding stability remains to be explored. To fill this gap, we synthesized and tested here the effect of 9 ER-, mitochondria- and lysosome-targeted chemical chaperones on the folding stability of truncated monomeric SOD1 (SOD1bar) mutants directed to those organelles. We found that compound ER-15 specifically increased the native state stability of ER-SOD1bar-A4V, while scaffold compound FDA-approved 4-phenylbutyric acid (PBA) decreased it. Furthermore, our results suggested that ER15 mechanism of action is distinct from that of PBA, opening new therapeutic perspectives of this novel chemical chaperone on ALS treatment.

中文翻译：

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细胞内空间靶向化学伴侣增加突变体 SOD1 桶的天然状态稳定性

肌萎缩侧索硬化症（ALS）是一种进行性神经系统疾病，目前无法治愈。与这种致命性蛋白质病相关的细胞功能障碍的核心是未折叠/错误折叠的超氧化物歧化酶 1 (SOD1) 在各个亚细胞位置的积累。驱动 SOD1 聚集体形成的分子机制尚不完全清楚，但大量研究表明，异常聚集随着突变 apoSOD1 的折叠不稳定性而升级。将细胞器靶向疗法与化学伴侣的抗聚集能力相结合的最新进展已成功减少错误折叠/聚集的 SOD1 的亚细胞负荷及其下游的低浓度（微摩尔范围）异常细胞过程。然而，这种局部聚集体的减少是否与折叠稳定性的增加直接相关仍有待探索。为了填补这一空白，我们在这里合成并测试了 9 种针对 ER、线粒体和溶酶体的化学伴侣对截短单体 SOD1 (SOD1) 折叠稳定性的影响。酒吧）针对这些细胞器的突变体。我们发现化合物 ER-15 特异性提高了 ER-SOD1 的天然状态稳定性酒吧-A4V，而 FDA 批准的支架化合物 4-苯基丁酸 (PBA) 则降低了它。此外，我们的结果表明，ER15 的作用机制与 PBA 不同，为这种新型化学伴侣治疗 ALS 开辟了新的治疗视角。