PICALM modulates autophagy activity and tau accumulation
Open accessAbstract
Genome-wide association studies have identified several loci associated with Alzheimer’s disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo . Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover.
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The autophagic system and endosome/lysosome pathways are compromised in AD brains.
“Consistent with this, the autophagic system and endosome/lysosome pathways are compromised in AD brains, and chronic disturbance of this system is thought to contribute to protein accumulation and neurodegeneration [85–87].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [87]
The paper’s introductory discussion (page not available) describes excess autophagosomes in affected AD neurons and suggests defects in their removal. Its Discussion links altered autophagy to tau accumulation and possible neurodegeneration. It does not establish that endosome/lysosome pathways themselves are compromised in AD brains; its evidence about those pathways concerns how CALM regulates autophagy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPICALM functions are central to its role in the clearance of both tau through autophagy and Aβ via transvascular transport across the BBB.
“These functions are central to its role in the clearance of both tau through autophagy (423) and A 𝛃 via transvascular transport across the BBB (683).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [423]
Chronic disturbance of the autophagic/endosome-lysosome system is thought to contribute to protein accumulation and neurodegeneration.
“Consistent with this, the autophagic system and endosome/lysosome pathways are compromised in AD brains, and chronic disturbance of this system is thought to contribute to protein accumulation and neurodegeneration [85–87].”
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- Authors
- Moreau, K., Fleming, A., Imarisio, S., Lopez Ramirez, A., Mercer, J. L., Jimenez-Sanchez, M., Bento, C. F., Puri, C., Zavodszky, E., Siddiqi, F., Lavau, C. P., Betton, M., O’Kane, C. J., Wechsler, D. S., & Rubinsztein, D. C.
- Affiliations
- University of Cambridge (GB)
- Duke University (US)
- Duke Medical Center (US)
- Corresponding author
- Rubinsztein, David C.
- ORCID
- Venue
- Nature Communications
- Published
- 2014-09-22
- Volume
- 5
- Issue
- 1
- Pages
- 4998-4998
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4199285
- OpenAlex
- W2142222850
- Cited by
- 281
- References
- 6
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 23 · 2023: 13 · 2022: 26 · 2021: 36 · 2020: 42 · 2019: 26 · 2018: 20 · 2017: 21 · 2016: 24 · 2015: 11 · 2014: 3 · 2013: 1
- FWCI
- 13.11
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-01-28)
- Open access
- hybrid
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (109281, 100140, 089703, 095317)
- University of Cambridge
- Universidad de Granada
- Tau Consortium
- Medical Research Council (MC_G1000734)
- Cambridge Institute for Medical Research, University of Cambridge
- Research Institute for Microbial Diseases, Osaka University
- National Cancer Institute (R01CA109281)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- PICALM, CALM, Alzheimer's disease, autophagy, tau accumulation, tau clearance, SNARE proteins, VAMP2, VAMP3, VAMP8, endocytosis, autophagosome formation, autophagosome degradation, genetic susceptibility loci
- MeSH terms
- Autophagy-Related Protein 12, Animals, Autophagy, Cell Line, Drosophila, Endocytosis, Female, Fibroblasts, HeLa Cells, Humans, Male, Phagosomes, Protein Binding, Risk Factors, Transfection, Zebrafish, tau Proteins, Small Ubiquitin-Related Modifier Proteins, Monomeric Clathrin Assembly Proteins, RNA, Small Interfering, Vesicle-Associated Membrane Protein 2, Mice, Genome-Wide Association Study, HEK293 Cells
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 ›
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