Department of Pharmacology and Chemical Biology

Figure 1. Overview of progranulin (PGRN) trafficking and production of neuroprotective granulins (GRNs) in the lysosome. PGRN is a glycoprotein that traffics through the trans-golgi network and is A) directly routed to the lysosome or B) secreted through exocytosis. PGRN can be endocytosed through the C) sortilin receptor and routed to lysosomes where PGRN is cleaved into GRN proteins (para and 1 through 7) by cathepsin proteases. PGRN also binds the prosaposin (PSAP) protein, which then binds the D) mannose-6-phosphate receptor to mediate lysosomal trafficking of both proteins. PSAP is processed into saposin (A-D) proteins that facilitate sphingolipid breakdown in the lysosome. We find that granulins are stable in the lysosome and suggest they have a beneficial and neuroprotective function. The precise function of granulins in the lysosome is unknown and is an active area of investigation in the Kukar lab.