Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher’s disease, characterized by <15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson’s disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient–derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD.

中文翻译：

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PIKfyve 调节剂与集成应激反应抑制剂相结合治疗溶酶体贮积症


溶酶体降解途径协调多余和受损细胞成分的清除。溶酶体降解受损是许多退行性疾病的标志，包括溶酶体贮积病 (LSD)，这是由溶酶体水解酶的两个等位基因内的功能丧失突变引起的，导致溶酶体底物积累。戈谢病的特征是葡萄糖脑苷脂酶功能正常，为 3C15%，是最常见的 LSD，也是患帕金森病的一个重要危险因素。在这里，我们表明，在高通量细胞脂滴清除筛选中鉴定出的两种结构不同的调节 PIKfyve 活性的小分子中的任何一种都可以通过促进溶酶体基因的 MiT/TFE 转录因子来改善戈谢病患者来源的成纤维细胞中的葡萄糖脑苷脂酶功能翻译。与 PIKfyve 调节剂组合使用的综合应激反应 (ISR) 拮抗剂可进一步提高细胞葡萄糖脑苷脂酶活性，这可能是因为 ISR 信号传导似乎也通过任一小分子在较高剂量下的治疗而被轻微激活。这种将 PIKfyve 调节剂与 ISR 抑制剂相结合的策略改善了额外 LSD 细胞模型中的突变溶酶体水解酶功能。