Gangliosides (GGs) are glycosphingolipids in which oligosaccharide chains containing N-acetylneuraminic acid (NeuNAc) are attached to a ceramide. Produced in the Golgi, they locate to the plasma membrane, where they contribute to Ca2+ and protein-ligand binding and to the ability of patches of the membrane to experience high curvature topologies, which is essential in many neuronal cells. Degradation of complex polysialylgangliosides starts during endocytosis producing GM1. Inward budding of the late endosomal membrane yields intralysosomal luminal vesicles (ILV) that carry the GGs on the outside of their membranes for final degradation and release to the cytosol. Essential cofactors for lysosomal ganglioside catabolism are the saposins, small carrier proteins which make GGs soluble by providing lipid anchors to move GGs from ILV membranes to the lysosome lumen. Another cofactor is the Ganglioside GM2 activator (GM2A, GM2AP), which is essential for beta-hexosaminidase activity in the degradation of GM2, GA2, and SM2A. Further cofactors appear to be membrane lipids including cholesterol. Lack of any participating enzyme or cofactor leads to the accumulation of glycosphingolipids in lysosomes and sphingolipidoses, including Gaucher's and Niemann–Pick diseases (reviewed in Kolter & Sandhoff, 2010; Sandhoff, 2016; Sandhoff & Sandhoff, 2018; Sandhoff et al., 2018; Breiden & Sandhoff, 2020).