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
  • Michael R Kreutz


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.

Bibliografische Daten

StatusVeröffentlicht - 29.11.2019
PubMed 31784514