Lysosomal Proteolysis and Autophagy Do Not Require Presenilins

Mutations in genes for presenilins (PS1 and PS2) lead to early-onset familial Alzheimer’s disease (FAD). It was recently shown that PS1 is required for macroautophagy in mouse blastocysts, and lysosomal proteolysis was proposed as a potential therapeutic target in FAD. Zhang et al. have meticulously tested that hypothesis and found it flawed. The previous work asserted that in cells lacking PS1 (PS1ko-ES), the proton-translocating V0a1 subunit of the vacuolar (H )ATPase failed to mature and transport to the lysosome; that lysosomes failed to acidify; and that macroautophagy was impaired compared to normal cells. In contrast, Zhang et al. report that vesicular pH and V0a1 maturation and processing were indistinguishable in wild-type and PS1null cells and brains, and that autophagic processes were robustly intact. Transcriptome analysis, however, showed that gene expression in the Coordinated Lysosomal Expression and Regulation (CLEAR) network was affected by PS1, hinting at a role for PS1 in lysosome biogenesis.