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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagosomes / metabolism*
  • Axonal Transport
  • Axons / metabolism
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Dyneins / metabolism
  • Endosomes / metabolism*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Hippocampus
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism*
  • Neuronal Plasticity / genetics*
  • Neurons / metabolism*
  • Presynaptic Terminals / metabolism*
  • Protein Transport
  • Protein-Tyrosine Kinases / metabolism*


  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • GTPase-Activating Proteins
  • Map1lc3b protein, mouse
  • Membrane Glycoproteins
  • Microtubule-Associated Proteins
  • sipa1l2 protein, mouse
  • Ntrk2 protein, mouse
  • Protein-Tyrosine Kinases
  • Dyneins