Universiteit Leiden

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Photocleavable activity-based acid glucosylceramidase probes

Lysosomal acid glucosylceramidase (GBA1) is a lysosomal enzyme that degrades glucolipids with its main substrate being glucosylceramide (GlcCer). Defects in the GBA1 gene lead to glycosphingolipidosis Gaucher disease (GD), in which the hydrolysis of GlcCer is impaired and therefore, it accumulates in the lysosome.

N.E. Trenkler
30 november 2023
Thesis in Leiden Repository

GD has a wide range of phenotypes that reaches from asymptomatic to neuropathologic manifestations, which are lethal within the first years of life. Although various GBA1 mutations have been identified, they cannot be systematically matched with GD phenotypes. Therefore, this thesis aims to get a better understanding of GBA1 and its role in GD by identifying GBA1’s cellular interaction partners with the aid of an enrichment assay. For this assay, photocleavable activity-based probes (ABPs) were developed, which ought to be able to isolate GBA1 from a cell lysate together with its interaction partners with the aid of streptavidin-coated beads. By photocleaving the complex off the beads, the background of the GBA1-containing samples can be lowered. So far, GBA1 could successfully be isolated from a cell lysate with the developed ABPs. Next, the assay conditions need to be optimized for isolation of GBA1 together with its interaction partners.

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