Glycosphingolipid catabolism

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).

神经节苷脂（GGs）是一种含有N-乙酰神经氨酸酸（NeuNAc）的寡糖链与神经酰胺相连的糖基鞘脂。它们在高尔基体中合成，定位于质膜，其中它们参与Ca2+和蛋白质-配体结合，并赋予膜斑能够体验高曲率拓扑结构的能力，这对于许多神经元细胞至关重要。复杂聚唾液酸神经节苷脂的降解始于内吞作用，产生GM1。晚期内吞膜的内向芽生产生内溶酶体腔泡（ILV），其膜外携带GGs，以便最终降解并释放到细胞质中。溶酶体神经节苷脂分解代谢的必需辅助因子是皂苷，这是一种小型载体蛋白，通过提供脂质锚定点，将GGs从ILV膜转运至溶酶体腔。另一个辅助因子是神经节苷脂GM2激活剂（GM2A，GM2AP），对于GM2、GA2和SM2A降解中的β-己糖胺酶活性至关重要。此外，膜脂质，包括胆固醇，似乎也是其他辅助因子。任何参与酶或辅助因子的缺乏都导致溶酶体中糖基鞘脂的积累，并引发脂质鞘氨醇病，包括戈谢病和尼曼-匹克病（参见Kolter & Sandhoff，2010；Sandhoff，2016；Sandhoff & Sandhoff，2018；Sandhoff等，2018；Breiden & Sandhoff，2020）。