BCM-95 and (2-hydroxypropyl)-β-cyclodextrin reverse autophagy dysfunction and deplete stored lipids in Sap C-deficient fibroblasts.
Saposin (Sap) C deficiency is a rare variant form of Gaucher disease caused by impaired Sap C expression or accelerated degradation, and associated with accumulation of glucosylceramide and other lipids in the endo/lysosomal compartment. No effective therapies are currently available for the treatment of Sap C deficiency. We previously reported that a reduced amount and enzymatic activity of cathepsin (Cath) B and Cath D, and defective autophagy occur in Sap C-deficient fibroblasts. Here, we explored the use of two compounds, BCM-95, a curcumin derivative, and (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), to improve lysosomal function of Sap C-deficient fibroblasts. Immunofluorescence and biochemical studies documented that each compound promotes an increase of the expression levels and activities of Cath B and Cath D, and efficient clearance of cholesterol (Chol) and ceramide (Cer) in lysosomes. We provide evidence that BCM-95 and HP-β-CD enhance lysosomal function promoting autophagic clearance capacity and lysosome reformation. Our findings suggest a novel pharmacological approach to Sap C deficiency directed to treat major secondary pathological aspects in this disorder.
Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
Massimo
M
Tatti
Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
Marialetizia
M
Motta
Department of Experimental Medicine, University of Rome 'La Sapienza', Viale Regina Elena, 324, 00161 Rome, Italy.
Susanna
S
Scarpa
Dulbecco Telethon Institute at the Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy and.
Sabrina
S
Di Bartolomeo
Dulbecco Telethon Institute at the Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy and Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark.
Valentina
V
Cianfanelli
Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
Marco
M
Tartaglia
Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy, rosa.salvioli@iss.it.
Rosa
R
Salvioli
D001343:Autophagy / Q000187:drug effects; D002401:Cathepsin B / Q000096:biosynthesis / Q000235:genetics; D002402:Cathepsin D / Q000096:biosynthesis / Q000235:genetics; D003474:Curcumin / Q000009:adverse effects* / Q000031:analogs & derivatives; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005776:Gaucher Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005963:Glucosylceramides / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000473:pathology; D049231:Saposins / Q000172:deficiency / Q000235:genetics*; D047392:beta-Cyclodextrins / Q000008:administration & dosage*
D005963:Glucosylceramides; D049231:Saposins; D047392:beta-Cyclodextrins; D002401:Cathepsin B; C533922:CTSD protein, human; D002402:Cathepsin D; D003474:Curcumin