Back to Search
Start Over
Pharmacological chaperones increase residual β-galactocerebrosidase activity in fibroblasts from Krabbe patients.
- Source :
-
Molecular genetics and metabolism [Mol Genet Metab] 2014 Aug; Vol. 112 (4), pp. 294-301. Date of Electronic Publication: 2014 May 23. - Publication Year :
- 2014
-
Abstract
- Krabbe disease or globoid cell leukodystrophy is a degenerative, lysosomal storage disease resulting from the deficiency of β-galactocerebrosidase activity. This enzyme catalyzes the lysosomal hydrolysis of galactocerebroside and psychosine. Krabbe disease is inherited as an autosomal recessive trait, and many of the 70 disease-causing mutations identified in the GALC gene are associated with protein misfolding. Recent studies have shown that enzyme inhibitors can sometimes translocate misfolded polypeptides to their appropriate target organelle bypassing the normal cellular quality control machinery and resulting in enhanced activity. In search for pharmacological chaperones that could rescue the β-galactocerebrosidase activity, we investigated the effect of α-Lobeline or 3',4',7-trihydroxyisoflavone on several patient-derived fibroblast cell lines carrying missense mutations, rather than on transduced cell lines. Incubation of these cell lines with α-lobeline or 3',4',7-trihydroxyisoflavone leads to an increase of β-galacocerebrosidase activity in p.G553R + p.G553R, in p.E130K + p.N295T and in p.G57S + p.G57S mutant forms over the critical threshold. The low but sustained expression of β-galactocerebrosidase induced by these compounds is a promising result; in fact, it is known that residual enzyme activity of only 15-20% is sufficient for clinical efficacy. The molecular interaction of the two chaperones with β-galactocerebrosidase is also supported by in silico analysis. Collectively, our combined in silico-in vitro approach indicate α-lobeline and 3',4',7-trihydroxyisoflavone as two potential pharmacological chaperones for the treatment or improvement of quality of life in selected Krabbe disease patients.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
COS Cells
Cell Survival drug effects
Chlorocebus aethiops
Computer Simulation
Fibroblasts drug effects
Fibroblasts pathology
Homozygote
Humans
Isoflavones chemistry
Isoflavones therapeutic use
Leukodystrophy, Globoid Cell drug therapy
Leukodystrophy, Globoid Cell pathology
Lobeline chemistry
Lobeline therapeutic use
Mice
Models, Molecular
Mutation, Missense genetics
Substrate Specificity
Fibroblasts enzymology
Galactosylceramidase metabolism
Isoflavones pharmacology
Leukodystrophy, Globoid Cell enzymology
Lobeline pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1096-7206
- Volume :
- 112
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular genetics and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 24913062
- Full Text :
- https://doi.org/10.1016/j.ymgme.2014.05.009