The normal functions of progranulin in the central nervous system remain to be defined, although studies have suggested a role of progranulin in promoting neuronal survival and regulating inflammation in the CNS. Moreover, mechanisms that regulate progranulin levels and the receptor and signaling pathways involved in progranulin action remain to be defined. Tolterodine tartrate Sortilin was recently identified as a progranulin binding partner in an expression cloning screen. Sortilin is a type I single pass transmembrane protein in the VPS10 family which regulates intracellular protein trafficking and acts as a cell surface receptor that mediates pro-NGF and pro-BDNF mediated cell death when coupled with p75/NTR. Sortilin mediates progranulin endocytosis and regulates the level of progranulin in the brain. The level of secreted progranulin is dramatically increased in sortilin knockout mice. Furthermore, ablation of sortilin is able to correct the decreased progranulin level in mice heterozygous for PGRN deletion. A genome wide association study has also found two SNPs close to sortilin that affect sortilin expression associated with PGRN level in the plasma. Thus progranulin-sortilin interaction is a major determinant of progranulin level in vivo. Here we report the mapping of the binding sites between progranulin and sortilin. We show that progranulin binds to the beta propeller region of sortilin through its C-terminal tail. The crystal structure of the VPS10 domain of sortilin was recently determined in a complex with another sortilin ligand, neurotensin. Neurotensin, a brain-gut tridecapeptide, interacts with the sortilin beta-propeller domain via its extreme carboxyl terminus. Our data suggests that progranulin and neurotensin interact with sortilin in a similar fashion. Since progranulin haplo-insufficiency is a leading cause of FTLD and sortilin is a main determinant of progranulin level, reagents that modulate progranulin-sortilin interaction and thus help restore progranulin levels in the brain might be of high therapeutic interest. Our study demonstrated a critical role of the progranulin Cterminal tail in mediating its interaction with sortilin and thus an important Naringin dihydrochalcone function of this fragment in controlling progranulin trafficking. This result will impact future experiments with progranulin gene therapy or protein administration to treat FTLD. By deleting the last 3 residues of progranulin, higher levels of progranulin in the brain could be possibly achieved by bypassing sortilin mediated regulation of progranulin trafficking and lysosomal degradation. However, it is still not clear whether the progranulinsortilin interaction also plays a role in progranulin signaling. Future studies are required to determine whether sortilin mediates the reported effects of progranulin on neuronal survival and inflammation. We have also found that the C-terminal carboxylate of progranulin in crucial in mediating the interaction between progranulin and sortilin.