Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration

Abstract

GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration.

FIGURE 1.

Schematic depicting the domain structure of progranulin. Boxed letters denote granulin domains. The NMR structure of granulin A according to coordinates deposited by Tolkatchev et al. (89) (MMDB ID 63884) is shown on top. Disulfide bridges are shown in orange, β-sheets in yellow, and the peptide backbone in green. Scissors denote elastase cleavage sites according to data presented by Zhu et al. (61). Asterisks denote linker regions where proteolytic cleavage also takes place, but the protease that releases granulins A and B has not been conclusively identified. The amino acid sequence of granulin A is shown at the bottom. Cysteines are highlighted in red. Numbers denote approximate positions of granulin domains relative to full-length human progranulin (593 residues).

FIGURE 2.

Trafficking of prosaposin and progranulin. Both prosaposin and progranulin consist of several repeats of saposin and granulin domains, respectively (step 1). Both proteins are N-glycosylated (step 2) and secreted (step 3). Prosaposin is also directly transported to the lysosomes (Lys) via the mannose 6-phosphate receptor (step 4). Sortilin also plays a role in lysosomal trafficking of prosaposin (not shown). Reuptake of progranulin is mediated by sortilin, whereas prosaposin reuptake is mediated by the LDL receptor-related protein (LRP), the mannose receptor (not shown), and the mannose 6-phosphate receptor (not shown) (step 5). Both proteins are probably proteolyzed intracellularly, although this has not been shown directly for progranulin (step 6). In the lysosome, the saposins activate lysosomal enzymes (pink pentagon) partly by lifting their substrates (green) out of the lipid bilayer (step 7). Lysosomal functions of granulins remain unknown. Prosaposin is shown in blue, progranulin is shown in red. ER, endoplasmic reticulum.