Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Aberrant lysosomal acidification mediates TRPML1 overactivation, resulting in dysregulation of lysosomal calcium ions, and solely reversing lysosomal calcium ion levels in cellular models failed to impact lysosomal acidity and autophagic function beneficially.
“Lee et al. once again affirmed the link between lysosomal acidification dysfunction and V-ATPase, further elucidating that aberrant lysosomal acidification mediates transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) overactivation, resulting in dysregulation of lysosomal calcium ions. Moreover, they demonstrated that solely reversing lysosomal calcium ion levels in”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [269]
The GBA substrates glucosylceramide (GlcCer) and its deacetylated derivative glucosylsphingosine (GlcSph) enhance nucleation of alpha-synuclein aggregates.
“The GBA substrates glucosylceramide (GlcCer) and its deacetylated derivative glucosylsphingosine (GlcSph) enhance nucleation of alpha-synuclein aggregates.”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [96]
The Introduction discusses presenilin 1, lysosomal function, and amyloid-beta, not whether GBA substrates promote alpha-synuclein aggregation. Searches for glucosylceramide, glucosylsphingosine, GlcCer, GlcSph, and aggregate nucleation found no passage in our copy addressing the claim; a synuclein-related reference does not establish it. (LLM, conf=0.75)
Experimental — accuracy not yet measuredReducing GlcCer levels by inhibiting GlcCer synthase reduces alpha-synuclein aggregation in mouse models of GD or PD.
“Reducing GlcCer levels by inhibiting GlcCer synthase reduces alpha-synuclein aggregation in mouse models of GD or PD.96,97”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [96]
The Introduction discusses lysosomal dysfunction in Parkinson’s disease and the therapeutic potential of lysosome modulation, but does not address GlcCer synthase inhibition or alpha-synuclein aggregation in GD or PD mouse models. Searches for those specific terms in our copy found no passage reporting the claimed result; page numbers were not provided. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 62 · Cited by 358
- Authors
- Lee, J.-H., McBrayer, M. K., Wolfe, D. M., Haslett, L. J., Kumar, A., Sato, Y., Lie, P. P. Y., Mohan, P., Coffey, E. E., Kompella, U., Mitchell, C. H., Lloyd-Evans, E., & Nixon, R. A.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- Cardiff University (GB)
- University of Pennsylvania (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Nixon, Ralph A.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 12
- Issue
- 9
- Pages
- 1430-1444
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4558203
- OpenAlex
- W1803199265
- Cited by
- 358
- References
- 62
- Citations by year
- 2026: 26 · 2025: 35 · 2024: 32 · 2023: 31 · 2022: 27 · 2021: 35 · 2020: 47 · 2019: 38 · 2018: 28 · 2017: 28 · 2016: 28 · 2015: 3
- FWCI
- 24.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Royal Society
- Research Councils UK
- National Institutes of Health
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (1086075)
- National Institute on Aging (P01AG017617)
- National Eye Institute (R01EY013434, R01EY015537)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- presenilin 1, TRPML1, lysosomal acidification, lysosomal proteolysis, autophagy, Alzheimer's disease, lysosomal pH, calcium efflux, glycosylation
- MeSH terms
- Animals, Autophagy, Calcium, Cell Line, Homeostasis, Hydrogen-Ion Concentration, Lysosomes, Vacuolar Proton-Translocating ATPases, Transient Receptor Potential Channels, Mice, Presenilin-1, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
