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

Patrick Lüningschrör,Annette Füchtbauer,Nurcan Üçeyler,Franziska Karl,Nadine Thau-Habermann,Arie Horowitz,Christian Kaltschmidt,Benjamin Dombert,Reinhard Jahn,Barbara Kaltschmidt,Carsten Slotta,Cora R Von Collenberg,Beyenech Binotti,Sibylle Jablonka,Robert Blum,Susanne Petri,Markus Damme,Peter Heimann,Ernst‐Martin Füchtbauer ,Ángel Pérez-Lara ,Isabelle Maystadt,Michael Sendtner

doi:10.1038/s41467-017-00689-z

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.

Highlights

Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis and constitutes a mechanism of neurodegeneration
Selective elimination of axon terminals marks disease onset in familial amyotrophic lateral sclerosis (ALS) and loss of synaptic vesicles precedes axon degeneration in SOD1 G93A mice[7], indicating that autophagy temporally regulates degradation of synaptic vesicles in axon terminals
We show that Plekhg[512–14] regulates autophagy of synaptic vesicles in motoneurons via its function as a guanine exchange factor (GEF) for Rab[26], a small GTPase selectively delivering synaptic vesicles into preautophagosomes[15]

Summary

Introduction

Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis and constitutes a mechanism of neurodegeneration. 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 Rab[26], a small GTPase that directs synaptic vesicles to preautophagosomal structures. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab[26] These findings define a mechanism for regulating autophagy in neurons that targets synaptic vesicles. Our data indicate that the function of Plekhg[5] as a GEF for Rab[26] is essential for axonal integrity, and that defective autophagy of synaptic vesicles is a pathogenic mechanism in this specific form of motoneuron disease

Methods

Results

Conclusion