A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases
成果类型：
Article
署名作者：
Hou, William C.; Massey, Lynee A.; Rhoades, Derek; Wu, Yin; Ren, Wen; Frank, Chiara; Overkleeft, Herman S.; Kelly, Jeffrey W.
署名单位：
Scripps Research Institute; Scripps Research Institute; Leiden University - Excl LUMC; Leiden University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-15131
DOI：
10.1073/pnas.2320257121
发表日期：
2024-08-20
关键词：
macrophage-targeted glucocerebrosidase
gaucher-disease
n-butyldeoxynojirimycin
autophagic degradation
therapeutic strategy
chemical chaperones
beta-glucosidase
lipid kinase
parkinsonism
mutations
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.