Cathepsin D and neuronal differentiation: lessons from the identification of a new binding partner

The identification of mutations in the gene coding for cathepsin D in human and animal cases of Neuronal Ceroid Lipofuscinosis (NCL), a progressive neurodegenerative disease characterized by the accumulation of autofluorescent cytoplasmic inclusions in the brain, neuronal loss, blindness and seizures, highlighted the importance to have an active and correctly targeted cathepsin D to sustain neuronal function. Interestingly, the characterization of mice that are deficient for the “classical lysosomal sorting machinery” (i.e. lacking the first enzyme that adds mannose 6-phosphate sorting signals on acid hydrolases) revealed that cathepsin D can be transported to the lysosomes by unknown mannose 6-phosphate- independent route(s) in the brain. To investigate these alternative transport route(s), and possibly highlight new mechanisms that could modulate the subcellular trafficking/activity of neuronal cathepsin D, we used affinity chromatography to search for the membrane binding partners of this hydrolase. This resulted in the identification of a member of a protein family that has been involved in neurite growth and synaptic maturation, the SEZ6 (Seizure-related gene 6) family. Using a combination of genetic and biochemical methods, we demonstrate that this member, SEZ6L2, is a protein that traffics to endosomes and participates to the subcellular trafficking of cathepsin D. Interestingly, our results reveal that the interaction of these two proteins modulates neurite outgrowth, thereby shedding additional light on the putative mechanisms that control neuronal differentiation.