PMID- 31784514 OWN - NLM STAT- MEDLINE DCOM- 20200310 LR - 20210110 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 10 IP - 1 DP - 2019 Nov 29 TI - SIPA1L2 controls trafficking and local signaling of TrkB-containing amphisomes at presynaptic terminals. PG - 5448 LID - 10.1038/s41467-019-13224-z [doi] LID - 5448 AB - 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. FAU - Andres-Alonso, Maria AU - Andres-Alonso M AD - Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany. AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Ammar, Mohamed Raafet AU - Ammar MR AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Butnaru, Ioana AU - Butnaru I AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Gomes, Guilherme M AU - Gomes GM AUID- ORCID: 0000-0001-8566-4284 AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Acuna Sanhueza, Gustavo AU - Acuna Sanhueza G AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Raman, Rajeev AU - Raman R AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Yuanxiang, PingAn AU - Yuanxiang P AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Borgmeyer, Maximilian AU - Borgmeyer M AD - Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany. FAU - Lopez-Rojas, Jeffrey AU - Lopez-Rojas J AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Raza, Syed Ahsan AU - Raza SA AD - Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University, 39120, Magdeburg, Germany. FAU - Brice, Nicola AU - Brice N AD - Paradigm Therapeutics Ltd. Cambridge, UK Cerevance, Cambridge, UK. FAU - Hausrat, Torben J AU - Hausrat TJ AD - Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany. FAU - Macharadze, Tamar AU - Macharadze T AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Diaz-Gonzalez, Silvia AU - Diaz-Gonzalez S AD - Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany. FAU - Carlton, Mark AU - Carlton M AD - Paradigm Therapeutics Ltd. Cambridge, UK Cerevance, Cambridge, UK. FAU - Failla, Antonio Virgilio AU - Failla AV AD - UKE Microscopy Imaging Facility, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. FAU - Stork, Oliver AU - Stork O AD - Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University, 39120, Magdeburg, Germany. AD - Center for Behavioral Brain Sciences, Otto von Guericke University, 39120, Magdeburg, Germany. FAU - Schweizer, Michaela AU - Schweizer M AD - ZMNH Core Facility Morphology and Electron Microscopy, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany. FAU - Gundelfinger, Eckart D AU - Gundelfinger ED AUID- ORCID: 0000-0001-9377-7414 AD - Center for Behavioral Brain Sciences, Otto von Guericke University, 39120, Magdeburg, Germany. AD - Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. AD - Medical Faculty, Otto von Guericke University, 39120, Magdeburg, Germany. FAU - Kneussel, Matthias AU - Kneussel M AD - Institute of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany. FAU - Spilker, Christina AU - Spilker C AUID- ORCID: 0000-0002-7996-7673 AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. FAU - Karpova, Anna AU - Karpova A AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. akarpova@lin-magdeburg.de. AD - Center for Behavioral Brain Sciences, Otto von Guericke University, 39120, Magdeburg, Germany. akarpova@lin-magdeburg.de. FAU - Kreutz, Michael R AU - Kreutz MR AD - 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. AD - RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany. michael.kreutz@lin-magdeburg.de. AD - Center for Behavioral Brain Sciences, Otto von Guericke University, 39120, Magdeburg, Germany. michael.kreutz@lin-magdeburg.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191129 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Bdnf protein, mouse) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (GTPase-Activating Proteins) RN - 0 (Map1lc3b protein, mouse) RN - 0 (Membrane Glycoproteins) RN - 0 (Microtubule-Associated Proteins) RN - 0 (sipa1l2 protein, mouse) RN - EC 2.7.10.1 (Ntrk2 protein, mouse) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 3.6.4.2 (Dyneins) SB - IM MH - Animals MH - Autophagosomes/*metabolism MH - Axonal Transport MH - Axons/metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Dyneins/metabolism MH - Endosomes/*metabolism MH - GTPase-Activating Proteins/genetics/*metabolism MH - Hippocampus MH - Membrane Glycoproteins/*metabolism MH - Mice MH - Mice, Knockout MH - Microtubule-Associated Proteins/*metabolism MH - Neuronal Plasticity/*genetics MH - Neurons/*metabolism MH - Presynaptic Terminals/*metabolism MH - Protein Transport MH - Protein-Tyrosine Kinases/*metabolism PMC - PMC6884526 COIS- The authors declare no competing interests. EDAT- 2019/12/01 06:00 MHDA- 2020/03/11 06:00 PMCR- 2019/11/29 CRDT- 2019/12/01 06:00 PHST- 2019/03/01 00:00 [received] PHST- 2019/10/28 00:00 [accepted] PHST- 2019/12/01 06:00 [entrez] PHST- 2019/12/01 06:00 [pubmed] PHST- 2020/03/11 06:00 [medline] PHST- 2019/11/29 00:00 [pmc-release] AID - 10.1038/s41467-019-13224-z [pii] AID - 13224 [pii] AID - 10.1038/s41467-019-13224-z [doi] PST - epublish SO - Nat Commun. 2019 Nov 29;10(1):5448. doi: 10.1038/s41467-019-13224-z.