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

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Dokumenter

DOI

  • Patrick Lüningschrör, University Hospital Würzburg, Universität Bielefeld
  • ,
  • Beyenech Binotti, Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute)
  • ,
  • Benjamin Dombert, University Hospital Würzburg
  • ,
  • Peter Heimann, Universität Bielefeld
  • ,
  • Angel Perez-Lara, Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute)
  • ,
  • Carsten Slotta, Universität 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, Thomas Jefferson University
  • ,
  • Isabelle Maystadt, Institut de Pathologie et de Génétique
  • ,
  • Annette Füchtbauer
  • Ernst Martin Füchtbauer
  • Sibylle Jablonka, University Hospital Würzburg
  • ,
  • Robert Blum, University Hospital Würzburg
  • ,
  • Nurcan Üçeyler, University Hospital Würzburg
  • ,
  • Susanne Petri, Hannover Medical School
  • ,
  • Barbara Kaltschmidt, Universität Bielefeld
  • ,
  • Reinhard Jahn, Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute)
  • ,
  • Christian Kaltschmidt, Universität Bielefeld
  • ,
  • Michael Sendtner, University Hospital Würzburg

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.

OriginalsprogEngelsk
Artikelnummer678
TidsskriftNature Communications
Vol/bind8
Nummer1
Antal sider17
ISSN2041-1723
DOI
StatusUdgivet - 30 okt. 2017

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