PUBLICATION

PICALM modulates autophagy activity and tau accumulation

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.
ID
ZDB-PUB-140923-8
Date
2014
Source
Nature communications   5: 4998 (Journal)
Registered Authors
Fleming, Angeleen
Keywords
Alzheimer's disease, Autophagy, Pathogenesis
MeSH Terms
  • Mice
  • Fibroblasts/metabolism
  • Cell Line
  • Zebrafish
  • Drosophila
  • Male
  • Small Ubiquitin-Related Modifier Proteins/metabolism
  • tau Proteins/metabolism*
  • Animals
  • Monomeric Clathrin Assembly Proteins/metabolism*
  • HeLa Cells
  • Female
  • Risk Factors
  • RNA, Small Interfering/metabolism
  • Vesicle-Associated Membrane Protein 2/metabolism
  • Genome-Wide Association Study
  • Autophagy*
  • Endocytosis
  • Protein Binding
  • Transfection
  • HEK293 Cells
  • Phagosomes
  • Humans
(all 23)
PubMed
25241929 Full text @ Nat. Commun.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (2 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
cu3Tg/cu3Tgstandard conditionsDays 7-13
cu7Tg/cu7TgcontrolDays 7-13
cu7Tg/cu7Tgstandard conditionsDays 7-13
cu7Tg/cu7Tgchemical treatment: ammonium chlorideDays 7-13
cu7Tg/cu7Tgchemical treatment: sirolimusDays 7-13
cu7Tg/cu7Tgchemical treatment: wortmanninDays 7-13
1 - 6 of 6
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cu3TgTransgenic Insertion
    cu7TgTransgenic Insertion
      1 - 2 of 2
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      Human Disease / Model
      No data available
      Sequence Targeting Reagents
      No data available
      Fish
      Fish
      cu3Tg/cu3Tg
      cu7Tg/cu7Tg
      1 - 2 of 2
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      Antibodies
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
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      Mapping
      No data available
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      Citation
      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. (2014) PICALM modulates autophagy activity and tau accumulation. Nature communications. 5:4998.