Sphingolipids, which function as plasma membrane lipids and signaling molecules, are highly enriched in neuronal and myelin membranes in the nervous system. They are degraded in lysosomes by a defined sequence of enzymatic steps. In the related group of disorders, the sphingolipidoses, mutations in the genes that encode the individual degradative enzymes cause lysosomal accumulation of sphingolipids and often result in severe neurodegenerative disease. Here we review the information indicating that microglia, which actively clear sphingolipid-rich membranes in the brain during development and homeostasis, are directly affected by these mutations and promote neurodegeneration in the sphingolipidoses. We also identify parallels between the sphingolipidoses and more common forms of neurodegeneration, which both exhibit evidence of defective sphingolipid clearance in the nervous system.

鞘脂作为质膜脂质和信号分子，在神经系统的神经元和髓鞘膜中高度富集。它们在溶酶体中通过定义的酶促步骤顺序降解。在相关的一组疾病中，编码单个降解酶的基因突变导致鞘脂在溶酶体中积累，并经常导致严重的神经退行性疾病。在这里，我们回顾了表明在发育和稳态过程中积极清除大脑中富含鞘脂的膜的小胶质细胞直接受到这些突变的影响并促进鞘脂中的神经变性的信息。我们还确定了鞘脂与更常见的神经退行性变之间的相似之处，