葡萄糖脑苷酶
溶酶体贮存病
溶酶体
细胞生物学
功能(生物学)
基质还原疗法
突变体
水解酶
转录因子
生物
化学
酶
生物化学
基因
疾病
内科学
酶替代疗法
医学
作者
William C. Hou,Lynée A. Massey,Derek Rhoades,Yaoping Wu,Wen Ren,Carola Frank,Herman S. Overkleeft,Jeffery W. Kelly
标识
DOI:10.1073/pnas.2320257121
摘要
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.
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