Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

Presenilin 1 (PS1) deletion or Alzheimer’s disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit, causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in Presenilin 1 knockout (PS1KO) cells induces abnormal Ca2+ efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca2+. In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca2+ homeostasis, but correcting lysosomal Ca2+ deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss-of-function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca2+ homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism. [Display omitted] •PS1 is essential for V0a1 subunit glycosylation, stability, and vATPase assembly•PS1 deficiency depletes vATPase, impairing lysosomal acidification and proteolysis•Defective lysosome acidification in PS1KO cells causes lysosomal Ca2+ efflux•TRPML1 mediates lysosomal Ca2+ efflux and cytosolic Ca2+ elevation in PS1KO cells Lee et al. present evidence establishing that Presenilin 1 loss of function elevates lysosomal pH via loss of V0a1 vATPase subunits. Besides disrupting autophagy, elevated lysosomal pH hyperactivates the TRPML1 calcium channel, causing increased lysosomal calcium efflux and cytosolic calcium elevation, thus linking two AD-related presenilin phenotypes to vATPase deficiency.