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.

鞘脂具有质膜脂质和信号分子的作用，在神经系统的神经元膜和髓磷脂膜中高度丰富。它们在溶酶体中通过定义的酶促步骤序列被降解。在相关的一组疾病中，鞘脂沉积症、编码单个降解酶的基因突变会导致鞘脂在溶酶体中积聚，并常常导致严重的神经退行性疾病。在这里，我们回顾了一些信息，表明小胶质细胞在发育和稳态过程中主动清除大脑中富含鞘脂的膜，直接受到这些突变的影响，并促进鞘脂沉积症中的神经变性。我们还发现了鞘脂沉积症和更常见的神经变性形式之间的相似之处，两者都表现出神经系统中鞘脂清除缺陷的证据。