SIPA1L2 controls trafficking and local signaling of TrkB-containing amphisomes at presynaptic terminals

Maria Andres-Alonso,Mohamed Raafet Ammar,Mark Carlton,Syed Ahsan Raza,Gustavo Acuña Sanhueza,Guilherme M Gomes,Maximilian Borgmeyer,Silvia Diaz-Gonzalez,Ioana Butnaru,Tamar Macharadze,Pingan Yuanxiang,Jeffrey Lopez‐Rojas ,Michaela Schweizer,Matthias Kneussel,Torben J Hausrat,Christina Spilker,Anna Karpova,Rajeev Raman,Eckart D Gundelfinger,Nicola Brice,Oliver Stork,Antonio Virgilio Failla,Michael R Kreutz

doi:10.1038/s41467-019-13224-z

Abstract

Amphisomes are organelles of the autophagy pathway that result from the fusion of autophagosomes with late endosomes. While biogenesis of autophagosomes and late endosomes occurs continuously at axon terminals, non-degradative roles of autophagy at boutons are barely described. Here, we show that in neurons BDNF/TrkB traffick in amphisomes that signal locally at presynaptic boutons during retrograde transport to the soma. This is orchestrated by the Rap GTPase-activating (RapGAP) protein SIPA1L2, which connects TrkB amphisomes to a dynein motor. The autophagosomal protein LC3 regulates RapGAP activity of SIPA1L2 and controls retrograde trafficking and local signaling of TrkB. Following induction of presynaptic plasticity, amphisomes dissociate from dynein at boutons enabling local signaling and promoting transmitter release. Accordingly, sipa1l2 knockout mice show impaired BDNF-dependent presynaptic plasticity. Taken together, the data suggest that in hippocampal neurons, TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.

Highlights

Amphisomes are organelles of the autophagy pathway that result from the fusion of autophagosomes with late endosomes
The data suggest that retrograde axonal transport of BDNF/TrkB occurs in neuronal amphisomes that allow local control of TrkB signaling and are involved in plasticity-relevant local signaling at presynaptic boutons
A significant deficit was found when we assessed mossy fiber (MF) long-term potentiation (LTP), a form of plasticity presynaptically expressed at MF boutons of dentate gyrus (DG) granule cells (Fig. 1a, b)

Summary

Introduction

Amphisomes are organelles of the autophagy pathway that result from the fusion of autophagosomes with late endosomes. We show that SIPA1L2 associates with amphisomes, organelles from the autophagic pathway that result from the fusion of autophagosomes with late endosomes, that are positive for the late endosome marker Rab[7] as well as LC3 and TrkB This configuration allows LC3 to tightly control TrkB signaling via interaction with SIPA1L2, which increases the RapGAP activity and promotes Rap1/ERK inactivation. Presynaptic LTP induces a protein kinase A (PKA)-dependent dissociation of the SIPA1L2/Snapin complex from dynein intermediate chain (DIC) This increases dwelling time of the amphisome at presynaptic boutons and PKA phosphorylation of SIPA1L2 reduces RapGAP activity, enabling local TrkB signaling at boutons, which in turn promotes neurotransmitter release. The data suggest that retrograde axonal transport of BDNF/TrkB occurs in neuronal amphisomes that allow local control of TrkB signaling and are involved in plasticity-relevant local signaling at presynaptic boutons

Methods

Results

Conclusion