PICALM modulates autophagy activity and tau accumulation

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....

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Bibliographic Details
Published in:Nature communications 2014-09, Vol.5 (1), p.4998-4998, Article 4998
Main Authors: Moreau, Kevin, Fleming, Angeleen, Imarisio, Sara, Lopez Ramirez, Ana, Mercer, Jacob L, Jimenez-Sanchez, Maria, Bento, Carla F, Puri, Claudia, Zavodszky, Eszter, Siddiqi, Farah, Lavau, Catherine P, Betton, Maureen, O'Kane, Cahir J, Wechsler, Daniel S, Rubinsztein, David C
Format: Article
Language:English
Subjects:
Animals
Autophagy
Autophagy-Related Protein 12
Cell Line
Drosophila
Endocytosis
Female
Fibroblasts - metabolism
Genome-Wide Association Study
HEK293 Cells
HeLa Cells
Humans
Male
Mice
Monomeric Clathrin Assembly Proteins - metabolism
Phagosomes
Protein Binding
Risk Factors
RNA, Small Interfering - metabolism
Small Ubiquitin-Related Modifier Proteins - metabolism
tau Proteins - metabolism
Transfection
Vesicle-Associated Membrane Protein 2 - metabolism
Zebrafish
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Summary: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms5998