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PICALM modulates autophagy activity and tau accumulation

Author

Listed:
  • 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
    Development and Neuroscience, University of Cambridge)

  • Sara Imarisio

    (University of Cambridge)

  • Ana Lopez Ramirez

    (University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital
    Development and Neuroscience, University of Cambridge)

  • Jacob L. Mercer

    (Duke University Medical Center
    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
    University of Cambridge)

  • Cahir J. O’Kane

    (University of Cambridge)

  • Daniel S. Wechsler

    (Duke University Medical Center
    Duke University Medical Center)

  • David C. Rubinsztein

    (University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital)

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.

Suggested Citation

  • 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 & , 2014. "PICALM modulates autophagy activity and tau accumulation," Nature Communications, Nature, vol. 5(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5998
    DOI: 10.1038/ncomms5998
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