Genetic defects in the sphingolipid degradation pathway and their effects on microglia in neurodegenerative disease

Abstract

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.

Keywords: Aging; Alzheimer's disease; Microglia; Parkinson's disease; Sphingolipidoses; Sphingolipids.

Fig. 1.

Disorders resulting from mutational defects in the lysosomal sphingolipid degradation pathway. Oligosaccharide structures are illustrated by colored symbols. Substrate names are presented in gray rounded boxes, genes are presented in green text, and disorders are presented in boxed red arrows. An asterisk (*) identifies a disease predisposition associated with a gene variant.

Fig. 2.

The sphingolipid degradation pathway and microglia in neurodegenerative disease. Microglia function during both development and homeostasis to eliminate dying neurons, prune neuronal synapses, and clear myelin debris. To accomplish these functions, sphingolipid-rich membranes are acquired from exogenous sources through the lipid-sensing receptor TREM2 and then undergo lysosomal degradation within microglia. During aging and the diseases indicated, these microglial processes are accelerated. Gene mutations in the sphingolipid degradation pathway genes reduce catabolic capacity and lead to lysosomal storage of sphingolipids, causing intrinsic microglial defects (such as a dysfunctional endosome-lysosome system), as well as compromising homeostatic functions and inducing a pro-inflammatory phenotype that promotes neurodegeneration.