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PICALM modulates autophagy activity and tau accumulation.


Type

Article

Change log

Authors

Imarisio, Sara 
Mercer, Jacob L 

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.

Description

Keywords

Animals, Autophagy, Autophagy-Related Protein 12, Cell Line, Drosophila, Endocytosis, Female, Fibroblasts, Genome-Wide Association Study, HEK293 Cells, HeLa Cells, Humans, Male, Mice, Monomeric Clathrin Assembly Proteins, Phagosomes, Protein Binding, RNA, Small Interfering, Risk Factors, Small Ubiquitin-Related Modifier Proteins, Transfection, Vesicle-Associated Membrane Protein 2, Zebrafish, tau Proteins

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

5

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_G1000734)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (089703/Z/09/Z)
Wellcome Trust (095317/Z/11/A)
We are grateful for funding from a Wellcome Trust Principal Research Fellowship (D.C.R.), a Wellcome Trust/MRC Strategic Grant on Neurodegeneration (D.C.R., C.J.O’.K.), a Wellcome Trust Strategic Award to Cambridge Institute for Medical Research, Wellcome Trust Studentship (E.Z.), the Alzheimer’s disease Biomedical Research Unit and Addenbrooke’s Hospital, the Tau Consortium, a fellowship from University of Granada (A.L.R.), a V Foundation/Applebee’s Research Grant (D.S.W.) and NCI R01 CA 109281 (D.S.W.).