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

• DOI: 10.1016/j.celrep.2015.07.050
• Publication Date: 2015-08-20T17:17:45Z
• Authors: Ju-Hyun Lee; Mary Kate McBrayer; Devin M. Wolfe; Luke J. Haslett; Asok Kumar; Yutaka Sato; Pearl P.Y. Lie; Panaiyur Mohan; Erin E. Coffey; Uday Kompella; Claire H. Mitchell; Emyr Lloyd-Evans; Ralph A. Nixon
• Keywords: Homeostasis; Proteolysis; Proteostasis

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 instability of vATPase V0a1 subunit, causing deficient assembly function. We further demonstrate elevated pH in knockout (PS1KO) cells induces abnormal Ca(2+) efflux lysosomes mediated by TRPML1 elevates cytosolic Ca(2+). In WT cells, blocking activity knockdown either PS1 the subunit reproduces all these abnormalities. Normalizing PS1KO using acidic nanoparticles restores normal autophagy, homeostasis, but correcting deficits alone neither re-acidifies nor reverses proteolytic autophagic deficits. Our results indicate deficiency loss-of-function states causes lysosomal/autophagy contributes to cellular thus linking two AD-related pathogenic processes through a common molecular mechanism.