PICALM modulates autophagy activity and tau accumulation

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...

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Main Authors: Moreau, Kevin, Fleming, Angeleen, Imarisio, Sara, Lopez Ramirez, Ana, Mercer, Jacob L., Jimenez-Sanchez, Maria, Bento, Carla F., Puri, Claudia, Zavodszky, Eszter, Siddiqi, Farah, Lavau, Catherine P., Betton, Maureen, O’Kane, Cahir J., Wechsler, Daniel S., Rubinsztein, David C.
Format: Online
Language:English
Published: Nature Pub. Group 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199285/
id pubmed-4199285
recordtype oai_dc
spelling pubmed-41992852014-10-17 PICALM modulates autophagy activity and tau accumulation Moreau, Kevin Fleming, Angeleen Imarisio, Sara Lopez Ramirez, Ana Mercer, Jacob L. Jimenez-Sanchez, Maria Bento, Carla F. Puri, Claudia Zavodszky, Eszter Siddiqi, Farah Lavau, Catherine P. Betton, Maureen O’Kane, Cahir J. Wechsler, Daniel S. Rubinsztein, David C. 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. Nature Pub. Group 2014-09-22 /pmc/articles/PMC4199285/ /pubmed/25241929 http://dx.doi.org/10.1038/ncomms5998 Text en Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Moreau, Kevin
Fleming, Angeleen
Imarisio, Sara
Lopez Ramirez, Ana
Mercer, Jacob L.
Jimenez-Sanchez, Maria
Bento, Carla F.
Puri, Claudia
Zavodszky, Eszter
Siddiqi, Farah
Lavau, Catherine P.
Betton, Maureen
O’Kane, Cahir J.
Wechsler, Daniel S.
Rubinsztein, David C.
spellingShingle Moreau, Kevin
Fleming, Angeleen
Imarisio, Sara
Lopez Ramirez, Ana
Mercer, Jacob L.
Jimenez-Sanchez, Maria
Bento, Carla F.
Puri, Claudia
Zavodszky, Eszter
Siddiqi, Farah
Lavau, Catherine P.
Betton, Maureen
O’Kane, Cahir J.
Wechsler, Daniel S.
Rubinsztein, David C.
PICALM modulates autophagy activity and tau accumulation
author_facet Moreau, Kevin
Fleming, Angeleen
Imarisio, Sara
Lopez Ramirez, Ana
Mercer, Jacob L.
Jimenez-Sanchez, Maria
Bento, Carla F.
Puri, Claudia
Zavodszky, Eszter
Siddiqi, Farah
Lavau, Catherine P.
Betton, Maureen
O’Kane, Cahir J.
Wechsler, Daniel S.
Rubinsztein, David C.
author_sort Moreau, Kevin
title PICALM modulates autophagy activity and tau accumulation
title_short PICALM modulates autophagy activity and tau accumulation
title_full PICALM modulates autophagy activity and tau accumulation
title_fullStr PICALM modulates autophagy activity and tau accumulation
title_full_unstemmed PICALM modulates autophagy activity and tau accumulation
title_sort picalm modulates autophagy activity and tau accumulation
description 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.
publisher Nature Pub. Group
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199285/
_version_ 1613145524369620992

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