PT  - JOURNAL ARTICLE
AU  - Maria Andres-Alonso
AU  - Mohamed Raafet Ammar
AU  - Ioana Butnaru
AU  - Guilherme M. Gomes
AU  - Gustavo Acuna Sanhueza
AU  - Rajeev Raman
AU  - PingAn Yuanxiang
AU  - Maximilian Borgmeyer
AU  - Jeffrey Lopez-Rojas
AU  - Syed Ahsan Raza
AU  - Nicola Brice
AU  - Torben J. Hausrat
AU  - Tamar Macharadze
AU  - Silvia Diaz-Gonzalez
AU  - Mark Carlton
AU  - Antonio Virgilio Failla
AU  - Oliver Stork
AU  - Michaela Schweizer
AU  - Eckart D. Gundelfinger
AU  - Matthias Kneussel
AU  - Christina Spilker
AU  - Anna Karpova
AU  - Michael R. Kreutz
TI  - SIPA1L2 controls trafficking and signaling of TrkB-containing amphisomes at presynaptic terminals
AID  - 10.1101/556266
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 556266
4099  - http://biorxiv.org/content/early/2019/02/20/556266.short
4100  - http://biorxiv.org/content/early/2019/02/20/556266.full
AB  - Amphisomes are transient organelles that derive from fusion of autophagosomes with late endosomes. They rapidly transform into degradative autolysosomes, whereas non-degradative roles of the autophagic pathway have been barely described. Here we show that in neurons BDNF/TrkB receptor bearing Rab7 / Light chain 3 (LC3) - positive amphisomes signal at presynaptic boutons during retrograde trafficking to the soma. Local signaling and inward transport essentially require the Rap GTPase-activating (RapGAP) protein SIPA1L2, which directly binds to TrkB and Snapin to connect TrkB-containing amphisomes to dynein. Association with LC3 regulates the RapGAP activity of SIPA1L2 and thereby retrograde trafficking. Following induction of presynaptic plasticity amphisomes dissociate from dynein at boutons, and this enables local signaling and promotes transmitter release. Accordingly, sipa1l2 knockout mice show impaired BDNF-dependent presynaptic plasticity. Collectively, the data suggest that TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.