The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index.
Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease
Open accessAbstract
Gaucher disease is a lysosomal storage disorder caused by deficient lysosomal β-glucosidase (β-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 μM) 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 β-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 β-Glu activity, but not that of L444P, a less prevalent Gaucher disease variant. Incubation of isolated soluble WT enzyme with NN-DNJ reveals that β-Glu is stabilized against heat denaturation in a dose-dependent fashion. We propose that NN-DNJ chaperones β-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 β-Glu activity may be sufficient to achieve a therapeutic effect.
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Pharmacological chaperones: a new twist on receptor folding
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Self-citationGeneration of Specific Deoxynojirimycin-type Inhibitors of the Non-lysosomal Glucosylceramidase
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Protein misfolding in the endoplasmic reticulum as a conduit to human disease
Wang, M., & Kaufman, R. J. (2016) · Nature · doi:10.1038/nature17041 · Cited by 1,630
Biological and Chemical Approaches to Diseases of Proteostasis Deficiency
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Self-citationSphingolipid metabolism diseases
Kolter, T., & Sandhoff, K. (2006) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2006.05.027 · Cited by 367
Identification and Characterization of Ambroxol as an Enzyme Enhancement Agent for Gaucher Disease
Maegawa, G. H. B., Tropak, M. B., Buttner, J. D., Rigat, B. A., Fuller, M., Pandit, D., Tang, L., Kornhaber, G. J., Hamuro, Y., Clarke, J. T. R., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.012393 · Cited by 332
Gaucher disease: pathological mechanisms and modern management
Jmoudiak, M., & Futerman, A. H. (2005) · British Journal of Haematology · doi:10.1111/j.1365-2141.2004.05351.x · Cited by 288
Metadata
- Authors
- Sawkar, A. R., Cheng, W.-C., Beutler, E., Wong, C.-H., Balch, W. E., & Kelly, J. W.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2002-11-14
- Volume
- 99
- Issue
- 24
- Pages
- 15428-15433
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1758125525
- Cited by
- 503
- References
- 23
- FWCI
- 12.31
- Type
- journal article
- Language
- en
- Open access
- green
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- Sawkar, A. R., Cheng, W.-C., Beutler, E., Wong, C.-H., Balch, W. E., & Kelly, J. W. (2002). Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.192582899
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