The transport of most newly synthesised lysosomal hydrolases to lysosomes is mediated by the canonical mannose 6-phosphate (Man-6-P)-dependent pathway. There is a growing body of evidence, however, that suggests that there are also Man-6-P-independent sorting pathways for hydrolases to reach the lysosomes. Some of these pathways appear to differ depending on the hydrolase, the cell type and their relevance to cellular function. On page 557, Michel Jadot and colleagues investigate how one particular aspartic protease – cathepsin D – is sorted to lysosomes in the brain in the absence of a functional Man-6-P-dependent pathway. The authors first search for potential cathepsin-D-binding partners, and identify the type 1 transmembrane protein SEZ6L2, which specifically interacts with cathepsin D in neuronal cells. Moreover, the authors show that SEZ6L2 traffics to endosomes from the TGN and plasma membrane, and is involved in the Man-6-P-independent transport of cathepsin D. Interestingly, cathepsin-D-dependent proteolytic cleavage of SEZ6L2 generates a soluble fragment that stimulates neurite outgrowth, suggesting a connection between Man-6-P-independent lysosomal transport pathways and neuronal differentiation. These findings therefore highlight that SEZ6L2 can serve as a receptor to mediate the sorting of cathepsin D to endosomes, and that this sorting process might contribute to neuronal development.