title: PICALM modulates autophagy activity and tau accumulation.
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.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Moreau
authors.affiliation: 1] Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK [2] Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Angeleen
authors.initials: A
authors.lastname: Fleming
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Imarisio
authors.affiliation: 1] Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK [2] Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Lopez Ramirez
authors.affiliation: 1] Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Mercer
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Jimenez-Sanchez
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Carla F
authors.initials: CF
authors.lastname: Bento
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Puri
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Eszter
authors.initials: E
authors.lastname: Zavodszky
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Farah
authors.initials: F
authors.lastname: Siddiqi
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Lavau
authors.affiliation: 1] Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK [2] Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Maureen
authors.initials: M
authors.lastname: Betton
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Cahir J
authors.initials: CJ
authors.lastname: O'Kane
authors.affiliation: 1] Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wechsler
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy; D000071192:Autophagy-Related Protein 12; D002460:Cell Line; D004330:Drosophila; D004705:Endocytosis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D034041:Monomeric Clathrin Assembly Proteins / Q000378:metabolism*; D010588:Phagosomes; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D012307:Risk Factors; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D014162:Transfection; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism; D015027:Zebrafish; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C466624:ATG12 protein, human; D000071192:Autophagy-Related Protein 12; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D034741:RNA, Small Interfering; D025841:Small Ubiquitin-Related Modifier Proteins; C494807:VAMP2 protein, human; D050988:Vesicle-Associated Membrane Protein 2; D016875:tau Proteins