Fig. 2

Dysregulation of lysosomal acidification in a mouse model of infantile NCL. Schematic representation of endosomal sorting and trafficking of a critical subunit of v-ATPase, the proton pump that maintains acidic pH of the lysosomal lumen. We recently uncovered that V0a1 requires S-palmitoylation for its endosomal transport to the lysosomal membrane (see ref. [67]). In Cln1^-/- mice (right panel), the lack Ppt1 causes misrouting of V0a1 to the plasma membrane instead of its normal location on the lysosomal membrane as seen in WT mice (left panel). Note that in Cln1^-/- mice, Ppt1-deficiency impairs the dissociation of V0a1 from AP-2, preventing its interaction with AP-3, which is essential for its transport from the sorting endosome to the late endosomal/lysosomal membrane. Consequently, the V0a1–AP-2 complex is misrouted to the plasma membrane via recycling endosome. This defect impairs v-ATPase activity, thereby dysregulating lysosomal acidification in neurons and other cells in Cln1^-/- mice. Since lysosomal hydrolases require acid pH for optimal catalytic activity, we propose that elevated lysosomal pH contributes to neuropathology in Cln1^-/- mice and most likely in INCL patients