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

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 Horowitz, Isabelle Maystadt, Annette Füchtbauer, Ernst-Martin Füchtbauer, Sibylle Jablonka, Robert Blum, Nurcan Üçeyler, Susanne Petri, Barbara Kaltschmidt, Reinhard Jahn, Christian Kaltschmidt () and Michael Sendtner ()
Additional contact information
Patrick Lüningschrör: University Hospital Würzburg
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
Barbara Kaltschmidt: University of Bielefeld
Reinhard Jahn: Max Planck Institute for Biophysical Chemistry
Christian Kaltschmidt: University of Bielefeld
Michael Sendtner: University Hospital Würzburg

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00689-z

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