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Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease

Author

Listed:
  • Patrick Lüningschrör

    (University Hospital Würzburg
    University of Bielefeld)

  • Beyenech Binotti

    (Max Planck Institute for Biophysical Chemistry)

  • Benjamin Dombert

    (University Hospital Würzburg)

  • Peter Heimann

    (University of Bielefeld)

  • Angel Perez-Lara

    (Max Planck Institute for Biophysical Chemistry)

  • Carsten Slotta

    (University of Bielefeld)

  • Nadine Thau-Habermann

    (Hannover Medical School)

  • Cora R. von Collenberg

    (University Hospital Würzburg)

  • Franziska Karl

    (University Hospital Würzburg)

  • Markus Damme

    (Christian-Albrechts-Universität zu Kiel)

  • Arie Horowitz

    (Sidney Kimmel Medical College, Thomas Jefferson University)

  • Isabelle Maystadt

    (Centre de Génétique Humaine, Institut de Pathologie et de Génétique)

  • Annette Füchtbauer

    (Aarhus University)

  • Ernst-Martin Füchtbauer

    (Aarhus University)

  • Sibylle Jablonka

    (University Hospital Würzburg)

  • Robert Blum

    (University Hospital Würzburg)

  • Nurcan Üçeyler

    (University Hospital Würzburg)

  • Susanne Petri

    (Hannover Medical School
    Integrated Research and Treatment Center Transplantation (IFB-Tx) Hannover)

  • Barbara Kaltschmidt

    (University of Bielefeld
    University of Bielefeld)

  • Reinhard Jahn

    (Max Planck Institute for Biophysical Chemistry)

  • Christian Kaltschmidt

    (University of Bielefeld)

  • Michael Sendtner

    (University Hospital Würzburg)

Abstract

Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.

Suggested Citation

  • Patrick Lüningschrör & Beyenech Binotti & Benjamin Dombert & Peter Heimann & Angel Perez-Lara & Carsten Slotta & Nadine Thau-Habermann & Cora R. von Collenberg & Franziska Karl & Markus Damme & Arie H, 2017. "Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00689-z
    DOI: 10.1038/s41467-017-00689-z
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    Cited by:

    1. Emmanouela Kallergi & Akrivi-Dimitra Daskalaki & Angeliki Kolaxi & Come Camus & Evangelia Ioannou & Valentina Mercaldo & Per Haberkant & Frank Stein & Kyriaki Sidiropoulou & Yannis Dalezios & Mikhail , 2022. "Dendritic autophagy degrades postsynaptic proteins and is required for long-term synaptic depression in mice," Nature Communications, Nature, vol. 13(1), pages 1-23, December.

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