Gaucher disease is a lysosomal storage disorder caused by deficient lysosomal
beta-glucosidase (beta-Glu) activity. A marked decrease in
enzyme activity results in progressive accumulation of the substrate (
glucosylceramide) in macrophages, leading to hepatosplenomegaly,
anemia, skeletal lesions, and sometimes CNS involvement.
Enzyme replacement therapy for
Gaucher disease is costly and relatively ineffective for CNS involvement. Chemical chaperones have been shown to stabilize various
proteins against misfolding, increasing proper trafficking from the endoplasmic reticulum. We report herein that the addition of subinhibitory concentrations (10 microM) of
N-(n-nonyl)deoxynojirimycin (
NN-DNJ) to a fibroblast culture medium for 9 days leads to a 2-fold increase in the activity of N370S beta-Glu, the most common mutation causing
Gaucher disease. Moreover, the increased activity persists for at least 6 days after the withdrawal of the putative chaperone. The
NN-DNJ chaperone also increases WT beta-Glu activity, but not that of L444P, a less prevalent
Gaucher disease variant. Incubation of isolated soluble WT
enzyme with
NN-DNJ reveals that beta-Glu is stabilized against heat denaturation in a dose-dependent fashion. We propose that
NN-DNJ chaperones beta-Glu folding at neutral pH, thus allowing the stabilized
enzyme to transit from the endoplasmic reticulum to the Golgi, enabling proper trafficking to the lysosome. Clinical data suggest that a modest increase in beta-Glu activity may be sufficient to achieve a
therapeutic effect.