N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease

Gaucher disease (GD) is the most common form of sphingolipidosis and is caused by a defect of β-glucosidase (β-Glu). A carbohydrate mimic N-octyl-β-valienamine (NOV) is an inhibitor of β-Glu. When applied to cultured GD fibroblasts with F213I β-Glu mutation, NOV increased the protein level of the mu...

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Bibliographic Details
Published in:Biochimica et biophysica acta 2004-08, Vol.1689 (3), p.219-228
Main Authors: Lin, Hou, Sugimoto, Yuko, Ohsaki, Yuki, Ninomiya, Haruaki, Oka, Akira, Taniguchi, Miyako, Ida, Hiroyuki, Eto, Yoshikatsu, Ogawa, Seiichiro, Matsuzaki, Yuji, Sawa, Miwa, Inoue, Takehiko, Higaki, Katsumi, Nanba, Eiji, Ohno, Kousaku, Suzuki, Yoshiyuki
Format: Article
Language:English
Subjects:
beta-Glucosidase - metabolism
Blotting, Western
Cells, Cultured
Chaperone
Gaucher disease
Gaucher Disease - drug therapy
Glucosylceramide
Hexosamines - pharmacology
Humans
Up-Regulation - drug effects
Valienamine
β-glucosidase
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Summary:Gaucher disease (GD) is the most common form of sphingolipidosis and is caused by a defect of β-glucosidase (β-Glu). A carbohydrate mimic N-octyl-β-valienamine (NOV) is an inhibitor of β-Glu. When applied to cultured GD fibroblasts with F213I β-Glu mutation, NOV increased the protein level of the mutant enzyme and up-regulated cellular enzyme activity. The maximum effect of NOV was observed in F213I homozygous cells in which NOV treatment at 30 μM for 4 days caused a ∼6-fold increase in the enzyme activity, up to ∼80% of the activity in control cells. NOV was not effective in cells with other β-Glu mutations, N370S, L444P, 84CG and RecNciI. Immunofluorescence and cell fractionation showed localization of the F213I mutant enzyme in the lysosomes of NOV-treated cells. Consistent with this, NOV restored clearance of 14C-labeled glucosylceramide in F213I homozygous cells. F213I mutant β-Glu rapidly lost its activity at neutral pH in vitro and this pH-dependent loss of activity was attenuated by NOV. These results suggest that NOV works as a chemical chaperone to accelerate transport and maturation of F213I mutant β-Glu and may suggest a therapeutic value of this compound for GD.
ISSN:0925-4439
0006-3002
1879-260X
DOI:10.1016/j.bbadis.2004.03.007