Critical role for piccolo in synaptic vesicle retrieval

  1. Frauke Ackermann  Is a corresponding author
  2. Kay Oliver Schink
  3. Christine Bruns
  4. Zsuzsanna Izsvák
  5. F Kent Hamra
  6. Christian Rosenmund
  7. Craig Curtis Garner  Is a corresponding author
  1. German Center for Neurodegenerative Diseases (DZNE), Charité Medical University, Germany
  2. University of Oslo, Norway
  3. Max-Delbrück Center for Molecular Medicine in the Helmholtz Society, Germany
  4. University of Texas Southwestern, United States
  5. Charité-Universitätsmedizin Berlin, Germany

Abstract

Loss of function of the active zone protein Piccolo has recently been linked to a disease, Pontocerebellar Hypoplasia type 3, which causes brain atrophy. Here, we address how Piccolo inactivation in rat neurons adversely affects synaptic function and thus may contribute to neuronal loss. Our analysis shows that Piccolo is critical for the recycling and maintenance of synaptic vesicles. We find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by reduced synaptic recruitment of Pra1, known to interact selectively with the zinc finger domains of Piccolo. Importantly, over-expression of GTPase deficient Rab5 or the Znf1 domain of Piccolo restores the size and recycling of SV pools. These data provide a molecular link between the active zone and endosome sorting at synapses providing hints to how Piccolo contributes to developmental and psychiatric disorders.

Data availability

All data generated or analysed during this study are included in the manuscript.

Article and author information

Author details

  1. Frauke Ackermann

    German Center for Neurodegenerative Diseases (DZNE), Charité Medical University, Berlin, Germany
    For correspondence
    Frauke.Ackermann@dzne.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3037-8672
  2. Kay Oliver Schink

    Center for Cancer Biomedicine, Norwegian Radium Hospital, University of Oslo, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5903-4059
  3. Christine Bruns

    German Center for Neurodegenerative Diseases (DZNE), Charité Medical University, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Zsuzsanna Izsvák

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. F Kent Hamra

    Department of Obstetrics and Gynecology, University of Texas Southwestern, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Christian Rosenmund

    Institut für Neurophysiologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3905-2444
  7. Craig Curtis Garner

    German Center for Neurodegenerative Diseases (DZNE), Charité Medical University, Berlin, Germany
    For correspondence
    craig.garner@dzne.de
    Competing interests
    The authors declare that no competing interests exist.

Funding

Deutsche Forschungsgemeinschaft (SFB958)

  • Craig Curtis Garner

European Research Council (ERC Advanced)

  • Christian Rosenmund

Norwegian Cancer Society (early carrier development grant)

  • Kay Oliver Schink

National Institute of Health (R01HD053889 and R01HD061575)

  • F Kent Hamra

National Center for Research Resources (R24RR03232601)

  • F Kent Hamra

The Office of the Director (R24OD011108)

  • F Kent Hamra

European Research Council (ERC Advanced,ERC-2011-AdG 294742)

  • Zsuzsanna Izsvák

Bundesministerium für Bildung und Forschung (NGFN-2,NGFNplus - ENGINE)

  • Zsuzsanna Izsvák

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Hugo J Bellen, Baylor College of Medicine, United States

Ethics

Animal experimentation: All procedures for experiments involving animals, were approved by the animal welfare committee of Charité Medical University and the Berlin state government (protocol number: T0036/14, O0208/16).

Version history

  1. Received: March 6, 2019
  2. Accepted: May 9, 2019
  3. Accepted Manuscript published: May 10, 2019 (version 1)
  4. Version of Record published: May 29, 2019 (version 2)

Copyright

© 2019, Ackermann et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Frauke Ackermann
  2. Kay Oliver Schink
  3. Christine Bruns
  4. Zsuzsanna Izsvák
  5. F Kent Hamra
  6. Christian Rosenmund
  7. Craig Curtis Garner
(2019)
Critical role for piccolo in synaptic vesicle retrieval
eLife 8:e46629.
https://doi.org/10.7554/eLife.46629

Share this article

https://doi.org/10.7554/eLife.46629

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