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Cell Rep. 2015 Sep 1;12(9):1430-44. doi: 10.1016/j.celrep.2015.07.050. Epub 2015 Aug 20.

Presenilin 1 Maintains Lysosomal Ca(2+) Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification.

Author information

1
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University, New York, NY 10016, USA.
2
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA.
3
Division of Pathophysiology and Repair, Cardiff University, Cardiff CF10 3XQ, UK.
4
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Pathology, New York University, New York, NY 10016, USA.
5
Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Pharmaceutical Science and Ophthalmology, University of Colorado, Aurora, CO 80045, USA.
7
Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University, New York, NY 10016, USA; Department of Cell Biology, New York University, New York, NY 10016, USA. Electronic address: nixon@nki.rfmh.org.

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 Ca(2+) efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca(2+). 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 Ca(2+) homeostasis, but correcting lysosomal Ca(2+) 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 Ca(2+) homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism.

PMID:
26299959
PMCID:
PMC4558203
DOI:
10.1016/j.celrep.2015.07.050
[Indexed for MEDLINE]
Free PMC Article

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