Figure 10. A schematic drawing illustrating the proposed disease mechanism of FTLD with GRN mutations.

PGRN and PSAP are highly secreted by microglia and astrocytes. Through binding to sortilin on neuronal cell surface, PGRN facilitates neuronal uptake of extracellular PSAP. Lysosomal delivery of PSAP results in PSAP processing into individual saposins (SAPs), which helps maintain normal lysosomal function in neurons. PGRN mutations in FTLD results in reduced PGRN levels and thus less neuronal uptake of PSAP and reduced saposin levels in neuronal lysosomes, which leads to lysosomal dysfunction and eventually neuronal cell death and FTLD. PSAP receptors, LRP1 and M6PR, which mediates alternate pathways for PSAP lysosomal delivery, are not shown in the drawing.