Curcumin controls lysosomal acidification and exocytosis to ameliorate lysosomal cholesterol accumulation in Niemann-Pick type C disease

Background and purpose: Niemann-Pick type C disease (NPCD) is a rare and fatal lysosomal storage disorder. There are limited therapies for NPCD, although multiple small-molecule compounds have shown therapeutic potential for NPCD. Curcumin (CUR), a polyphenolic compound enriched in turmeric, has cholesterol-lowering effects via regulating intestinal Cholesterol absorption and liver Cholesterol synthesis. CUR normalises sphingolipid trafficking and stimulates exosome/microvesicle release, increases cytosolic CA²⁺ levels, and enhances lysosomal activation via mTOR suppression and TFEB activation. How CUR specifically targets lysosomal Cholesterol has not been fully clarified.

Experimental approach: Effects of curcumin on lysosomal Cholesterol accumulation were evaluated in NPC1 cell models. Filipin staining, immunofluorescence, surface LAMP1 and NAGase activity and Cathepsin B activity were investigated to evaluate lysosomal Cholesterol, TFEB translocation, lysosomal exocytosis and hydrolytic activity. Lysosomal acidification was determined by Lysotracker Red, Oregon Green, and sfGFP/mCherry transfection. CRISPR/Cas9 and siRNA interference were used to investigate the role of TFEB/TFE3 and TRPML1 in curcumin-induced Cholesterol reduction.

Key results: CUR alleviates lysosomal Cholesterol accumulation in NPC1 cells in a TFEB- and TFE3-dependent manner. CUR enhanced lysosomal acidity and promoted calcium-dependent lysosomal exocytosis, which contributed to CUR-mediated lysosomal Cholesterol clearance. The combination of CUR with specific agonists (ML-SAs) of MCOLN1/TRPML1, a lysosomal cation channel required for lysosomal exocytosis, improved lysosomal Cholesterol clearance.

Conclusion and implications: CUR reduces lysosomal Cholesterol accumulation in NPC1 cells by activating TFEB/TFE3 pathways and promoting CA²⁺- and TRPML1-dependent lysosomal exocytosis. These findings support curcumin and its analogues as potential therapeutics for NPCD and Other Diseases of lysosomal storage.