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

Maria Andres-Alonso, Mohamed Raafet Ammar, Ioana Butnaru, Guilherme M. Gomes, Gustavo Acuña Sanhueza, Rajeev Raman, PingAn Yuanxiang, Maximilian Borgmeyer, Jeffrey Lopez-Rojas, Syed Ahsan Raza, Nicola Brice, Torben J. Hausrat, Tamar Macharadze, Silvia Diaz-Gonzalez, Mark Carlton, Antonio Virgilio Failla, Oliver Stork, Michaela Schweizer, Eckart D. Gundelfinger, Matthias Kneussel, Christina Spilker, Anna Karpova () and Michael R. Kreutz ()
Additional contact information
Maria Andres-Alonso: University Medical Center Hamburg-Eppendorf
Mohamed Raafet Ammar: Leibniz Institute for Neurobiology
Ioana Butnaru: Leibniz Institute for Neurobiology
Guilherme M. Gomes: Leibniz Institute for Neurobiology
Gustavo Acuña Sanhueza: Leibniz Institute for Neurobiology
Rajeev Raman: Leibniz Institute for Neurobiology
PingAn Yuanxiang: Leibniz Institute for Neurobiology
Maximilian Borgmeyer: University Medical Center Hamburg-Eppendorf
Jeffrey Lopez-Rojas: Leibniz Institute for Neurobiology
Syed Ahsan Raza: Otto-von-Guericke University
Nicola Brice: UK Cerevance
Torben J. Hausrat: University Medical Center Hamburg-Eppendorf
Tamar Macharadze: Leibniz Institute for Neurobiology
Silvia Diaz-Gonzalez: University Medical Center Hamburg-Eppendorf
Mark Carlton: UK Cerevance
Antonio Virgilio Failla: University Medical Center Hamburg-Eppendorf
Oliver Stork: Otto-von-Guericke University
Michaela Schweizer: University Medical Center Hamburg-Eppendorf
Eckart D. Gundelfinger: Otto von Guericke University
Matthias Kneussel: University Medical Center Hamburg-Eppendorf
Christina Spilker: Leibniz Institute for Neurobiology
Anna Karpova: Leibniz Institute for Neurobiology
Michael R. Kreutz: University Medical Center Hamburg-Eppendorf

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13224-z

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