期刊
NATURE COMMUNICATIONS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms5998
关键词
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资金
- Wellcome Trust
- Wellcome Trust/MRC Strategic Grant on Neurodegeneration
- Alzheimer's disease Biomedical Research Unit
- Addenbrooke's Hospital
- Tau Consortium
- University of Granada
- V Foundation/Applebee's Research Grant
- NCI [R01 CA 109281]
- Medical Research Council [MC_G1000734] Funding Source: researchfish
- MRC [MC_G1000734] Funding Source: UKRI
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.
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