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Molecular probes

Getting lucky in the lysosome

Nature Chemical Biology volume 6, pages 881–883 (2010)Cite this article

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Conjugation of a known, mechanism-based glycosidase inhibitor to sensitive fluorophores yielded unexpectedly potent and selective probes for quantifying active lysosomal glucocerebrosidase. These conjugates could prove to be invaluable tools for diagnosing and studying Gaucher disease.

The majority of Gaucher disease–causing mutations in GBA impair intracellular trafficking of the enzyme, rather than affecting its inherent activity. These mutations compromise the ability of the enzyme to obtain and retain its native fold within the endoplasmic reticulum (ER), and so most of the mutant enzyme undergoes ER-associated degradation (ERAD) instead of being trafficked to its intended destination, the lysosome. Interestingly, individuals with just 10–15% of normal GBA activity levels are asymptomatic; thus, if the flux of the GBA mutant to the lysosome can be increased by even a small amount, the Gaucher disease pathologies may be ameliorated. Enzyme enhancement therapy (EET) seeks to do just this by using small-molecule chaperones, such as isofagomine, to bind and stabilize correctly folded mutant GBA within the ER, thereby elevating the steady-state concentration of folded enzyme within this organelle and increasing the amount of enzyme trafficked to lysosomes (Fig. 1b)2,3. A simple means to determine the amount of active GBA within cells would be of great value not only as a diagnostic tool but also in the development of such new therapies.

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Figure 1: Getting a grip on GBA.

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Authors and Affiliations

  1. Tom Wennekes and Stephen G. Withers are in the Department of Chemistry and Center for High-Throughput Biology, Ethan D. Goddard-Borger, University of British Columbia, Vancouver, British Columbia, Canada.,

    Ethan D Goddard-Borger, Tom Wennekes & Stephen G Withers

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  1. Ethan D Goddard-Borger
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  2. Tom Wennekes
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  3. Stephen G Withers
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Correspondence to Stephen G Withers.

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Goddard-Borger, E., Wennekes, T. & Withers, S. Getting lucky in the lysosome. Nat Chem Biol 6, 881–883 (2010). https://doi.org/10.1038/nchembio.470

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