BCM-95 and (2-hydroxypropyl)-ß-cyclodextrin reverse autophagy dysfunction and deplete stored lipids in Sap C-deficient fibroblasts.
Hum Mol Genet
; 24(15): 4198-211, 2015 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-25926625
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)-ß-cyclodextrin (HP-ß-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-ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Curcumina
/
Beta-Ciclodextrinas
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Saposinas
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Doença de Gaucher
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article