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.