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Nat Commun. 2019 Nov 29;10(1):5448. doi: 10.1038/s41467-019-13224-z.

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

Author information

1
Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.
2
RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany.
3
Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University, 39120, Magdeburg, Germany.
4
Paradigm Therapeutics Ltd. Cambridge, UK Cerevance, Cambridge, UK.
5
Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.
6
UKE Microscopy Imaging Facility, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
7
Center for Behavioral Brain Sciences, Otto von Guericke University, 39120, Magdeburg, Germany.
8
ZMNH Core Facility Morphology and Electron Microscopy, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.
9
Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany.
10
Medical Faculty, Otto von Guericke University, 39120, Magdeburg, Germany.
11
RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. akarpova@lin-magdeburg.de.
12
Center for Behavioral Brain Sciences, Otto von Guericke University, 39120, Magdeburg, Germany. akarpova@lin-magdeburg.de.
13
Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany. michael.kreutz@lin-magdeburg.de.
14
RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. michael.kreutz@lin-magdeburg.de.
15
Center for Behavioral Brain Sciences, Otto von Guericke University, 39120, Magdeburg, Germany. michael.kreutz@lin-magdeburg.de.

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.

PMID:
31784514
PMCID:
PMC6884526
DOI:
10.1038/s41467-019-13224-z
[Indexed for MEDLINE]
Free PMC Article

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