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Nat Commun. 2014 Sep 22;5:4998. doi: 10.1038/ncomms5998.

PICALM modulates autophagy activity and tau accumulation.

Author information

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
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.
3
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
4
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.
5
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
6
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.

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.

PMID:
25241929
PMCID:
PMC4199285
DOI:
10.1038/ncomms5998
[Indexed for MEDLINE]
Free PMC Article

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