The GTPase Rab26 links synaptic vesicles to the autophagy pathway.

Beyenech Binotti,Gerd Vorbrüggen,Dirk Wenzel,Christian Erck,Dietmar Riedel,John Je Chua,Janina Boyken,Reinhard Jahn,Henrik Martens,Karin Kühnel,Amanda M Schalk,Nathan J Pavlos

doi:10.7554/elife.05597

Abstract

Small GTPases of the Rab family not only regulate target recognition in membrane traffic but also control other cellular functions such as cytoskeletal transport and autophagy. Here we show that Rab26 is specifically associated with clusters of synaptic vesicles in neurites. Overexpression of active but not of GDP-preferring Rab26 enhances vesicle clustering, which is particularly conspicuous for the EGFP-tagged variant, resulting in a massive accumulation of synaptic vesicles in neuronal somata without altering the distribution of other organelles. Both endogenous and induced clusters co-localize with autophagy-related proteins such as Atg16L1, LC3B and Rab33B but not with other organelles. Furthermore, Atg16L1 appears to be a direct effector of Rab26 and binds Rab26 in its GTP-bound form, albeit only with low affinity. We propose that Rab26 selectively directs synaptic and secretory vesicles into preautophagosomal structures, suggesting the presence of a novel pathway for degradation of synaptic vesicles.

Highlights

Synapses are highly dynamic structures exhibiting frequent turnover
In the present study we have combined multiple complementary biochemical and cell biological approaches to demonstrate that the small GTPase Rab26 is associated with synaptic vesicles
Rab26 appears to be enriched in large clusters of synaptic vesicles to which the autophagy proteins Atg16L1, LC3 and Rab33B are recruited, suggesting that they represent pre-autophagosomal compartments

Summary

Introduction

Synapses are highly dynamic structures exhibiting frequent turnover. The most dramatic phase of synaptic remodeling occurs during development when the majority of initially formed synapses are eliminated while the final synaptic network is being generated. Even in the adult brain there is persistent turnover of synapses, mostly in response to experience and learning (Caroni et al, 2012; Chung and Barres, 2012). Formation of a new synapse involves the establishment of highly specialized structures containing arrays of unique membrane and scaffold proteins, which necessitates close coordination between the presynaptic axon and the postsynaptic dendrite. Components of these structures are delivered by microtubule-based transport, some of the proteins are locally synthesized in dendrites (Steward and Levy, 1982; Holt and Schuman, 2013). A lot has been learned in recent years about the signaling events and the downstream effectors involved in synaptogenesis as well as the mechanisms by which individual components are recruited and maintained (Caroni et al, 2012)

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