PICALM modulates autophagy activity and tau accumulation

Kevin Moreau, Angeleen Fleming, Sara Imarisio, Ana Lopez Ramirez, Jacob L. Mercer, Maria Jimenez-Sanchez, Carla F. Bento, Claudia Puri, Eszter Zavodszky, Farah Siddiqi, Catherine P. Lavau, Maureen Betton, Cahir J. O’Kane, Daniel S. Wechsler and David C. Rubinsztein ()
Additional contact information
Kevin Moreau: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Angeleen Fleming: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Sara Imarisio: University of Cambridge
Ana Lopez Ramirez: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Jacob L. Mercer: Duke University Medical Center
Maria Jimenez-Sanchez: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Carla F. Bento: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Claudia Puri: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Eszter Zavodszky: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Farah Siddiqi: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Catherine P. Lavau: Duke University Medical Center
Maureen Betton: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Cahir J. O’Kane: University of Cambridge
Daniel S. Wechsler: Duke University Medical Center
David C. Rubinsztein: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital

Nature Communications, 2014, vol. 5, issue 1, 1-20

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5998

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