Un(der)recognized glucosylceramide metabolites: their occurrence, their biological functions and their role in human pathologies

Glucosylceramide (GlcCer) is a ubiquitous cellular building block that fulfils important, but in some aspects little appreciated, roles in health and disease. We aim to obtain fundamental insight in GlcCer metabolism in its broadest sense and generate new biomarkers and diagnostics, and ultimately new therapeutics. Well-known GlcCer metabolites are complex glycosphingolipids implicated in signaling processes. Their excess is associated with Metabolic Syndrome. A less studied GlcCer metabolite is glucosylsphingosine, recently shown to induce Multiple Myeloma. Additional GlcCer metabolites are glucosylated sterols and other glucosylated metabolites that emerge after transfer of glucose from GlcCer. During inherited deficiency of glucosylceramidase GBA1 (Gaucher disease, a multi-organ lysosomal storage disease), GlcCer and its metabolites accumulate. Impaired GBA1 constitutes a known but unexplained risk for Parkinsonism. Pathological consequences of excessive glucosylation of sterols and other metabolites warrant elucidation. We plan to identify glucosylated metabolites of GlcCer and obtain structural and spatio-temporal insight in GlcCer metabolism by glycosidases. The aim is to understand the cellular consequences of GlcCer metabolites as a first step towards manipulating the associated diseases. Assembled is an interdisciplinary platform with input from synthetic organic chemistry, cell biology, structural biology, medical biochemistry and industry to dissect GlcCer metabolism from various angles.