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PICALM modulates autophagy activity and tau accumulation.



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Imarisio, Sara 
Mercer, Jacob L 


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.



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

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Nat Commun

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Springer Science and Business Media LLC
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.).