Presenilin 1 maintains Lysosomal Ca2+ homeostasis via TRPML1 by regulating vATPase-mediated lysosome acidification

Lee, Ju-Hyun, McBrayer, Mary Kate, Wolfe, Devin M., Haslett, Luke J., Kumar, Asok, Sato, Yutaka, Lie, Pearl P.Y., Mohan, Panaiyur, Coffey, Erin E., Kompella, Uday, Mitchell, Claire H., Lloyd-Evans, Emyr ORCID: https://orcid.org/0000-0002-3626-1611 and Nixon, Ralph A. 2015. Presenilin 1 maintains Lysosomal Ca2+ homeostasis via TRPML1 by regulating vATPase-mediated lysosome acidification. Cell Reports 12 (9) , pp. 1430-1444. 10.1016/j.celrep.2015.07.050

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Additional Information:	This is an open access article under the terms of the CC-BY Attribution 4.0 International license.
Publisher:	Elsevier
ISSN:	2211-1247
Date of First Compliant Deposit:	15 March 2019
Date of Acceptance:	24 July 2015
Last Modified:	05 May 2023 03:51
URI:	https://orca.cardiff.ac.uk/id/eprint/77213

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