PICALM modulates autophagy activity and tau accumulation

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. Corrigendum: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341252/