PICALM modulates autophagy activity and tau accumulation.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Moreau, K; Fleming, A; Imarisio, S; Lopez Ramirez, A; Mercer, JL; Jimenez-Sanchez, M; Bento, CF; Puri, C; Zavodszky, E; Siddiqi, F; Lavau, CP; Betton, M; O'Kane, CJ; Wechsler, DS; Rubinsztein, DC

Published Date

  • September 22, 2014

Published In

Volume / Issue

  • 5 /

Start / End Page

  • 4998 -

PubMed ID

  • 25241929

Pubmed Central ID

  • 25241929

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms5998

Language

  • eng