Gangliosides are the main
glycolipids of neuronal plasma membranes. Their surface patterns are generated by coordinated processes, involving biosynthetic pathways of the secretory compartments, catabolic steps of the endolysosomal system, and intracellular trafficking. Inherited defects in
ganglioside biosynthesis causing fatal
neurodegenerative diseases have been described so far almost exclusively in mouse models, whereas inherited defects in
ganglioside catabolism causing various clinical forms of GM1- and GM2-gangliosidoses have long been known. For digestion,
gangliosides are endocytosed and reach intra-endosomal vesicles. At the level of late endosomes, they are depleted of membrane-stabilizing
lipids like
cholesterol and enriched with
bis(monoacylglycero)phosphate (BMP). Lysosomal catabolism is catalyzed at acidic pH values by cationic
sphingolipid activator proteins (SAPs), presenting
lipids to their respective
hydrolases, electrostatically attracted to the negatively charged surface of the
luminal BMP-rich vesicles. Various inherited defects of
ganglioside hydrolases, e.g., of β-
galactosidase and β-
hexosaminidases, and of GM2-activator
protein, cause infantile (with tetraparesis,
dementia,
blindness) and different protracted clinical forms of GM1- and GM2-gangliosidoses. Mutations yielding
proteins with small residual catabolic activities in the lysosome give rise to juvenile and adult clinical forms with a wide range of clinical symptomatology. Apart from patients' differences in their genetic background, clinical heterogeneity may be caused by rather diverse substrate specificities and functions of lysosomal
hydrolases, multifunctional properties of SAPs, and the strong regulation of
ganglioside catabolism by
membrane lipids. Currently, there is no treatment available for neuronal
ganglioside storage diseases. Therapeutic approaches in mouse models and patients with juvenile forms of
gangliosidoses are discussed.