BCM-95 and (2-hydroxypropyl)-β-cyclodextrin reverse autophagy dysfunction and deplete stored lipids in Sap C-deficient fibroblasts.

Abstract

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.

• Authors: Massimo Tatti, Marialetizia Motta, Susanna Scarpa, Sabrina Di Bartolomeo, Valentina Cianfanelli, Marco Tartaglia, Rosa Salvioli
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 15 Pg. 4198-211 (Aug 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25926625 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Glucosylceramides
• Saposins
• beta-Cyclodextrins
• Cathepsin B
• CTSD protein, human
• Cathepsin D
• Curcumin

Topics

• Autophagy (drug effects)
• Cathepsin B (biosynthesis, genetics)
• Cathepsin D (biosynthesis, genetics)
• Curcumin (adverse effects, analogs & derivatives)
• Fibroblasts (metabolism, pathology)
• Gaucher Disease (drug therapy, genetics, pathology)
• Glucosylceramides (metabolism)
• Humans
• Lysosomes (genetics, pathology)
• Saposins (deficiency, genetics)
• beta-Cyclodextrins (administration & dosage)