Reorchestrating glycosphingolipid metabolism by targeting glycosidases and glycosyltransferases

Abstract

Glycosphingolipids are essential components of human cells. They are synthesised by stepwise glycosylation in the Golgi complex, after which they are trafficked to the compartment in the cell to fulfil their function. Eventually, they are trafficked to the lysosome for degradation and recycling of their components. In the case of a deficiency of one of the enzymes responsible for degradation of these glycosphingolipids, its substrate accumulates, causing a lysosomal storage disorder. Therapeutic strategies are 1) enzyme replacement therapy, which is efficacious for some patients but less efficacious for others; 2) substrate reduction therapy, in which the glycosyltransferase that synthesizes the accumulating metabolite is inhibited, which is an inherently challenging avenue; or 3) pharmacological chaperone therapy, in which the deficient enzyme is stabilized, but which is also efficacious for a certain subpopulation of patients. This Thesis describes three therapeutic strategies: 1) selective inactivation of non-lysosomal glucosylceramidase, an important and therapeutically relevant glycosidase that is thought to be involved in neuroinflammation; 2) targeted protein degradation of non-lysosomal glucosylceramidase and glycosylceramide synthase, a target for substrate reduction therapy; and 3) targeted protein degradation of Golgi-located targets for substrate reduction therapy.