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Haploinsufficiency of the progranulin protein is a leading cause of frontotemporal lobar degeneration. Accumulating evidence support a crucial role of progranulin in the lysosome. Progranulin comprises 7.5 granulin repeats and is known to traffic to lysosomes via direct interactions with prosaposin or sortilin. Within the lysosome, progranulin gets processed into granulin peptides. Here, we report that sortilin and prosaposin independently regulate lysosomal trafficking of progranulin in vivo. The deletion of either prosaposin or sortilin alone results in a significant decrease in the ratio of granulin peptides versus full-length progranulin in mouse brain lysates. This decrease is further augmented by the deficiency of both prosaposin and sortilin. A concomitant increase in the levels of secreted progranulin in the serum was observed. Interestingly, while the deletion of both prosaposin and sortilin totally abolishes …