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

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.

Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum

“…Among these mechanisms are lysosomal turnover of membrane proteins and autophagy, a cellular process by which defective proteins and organelles are degraded through sequestration in autophagosomes and delivery to lysosomes ( Hill and Colón-Ramos, 2020 ; Nikoletopoulou and Tavernarakis, 2018 ; Vijayan and Verstreken, 2017 ). In neurons, autophagy has been implicated in diverse processes ranging from development, including signaling via neurotrophins ( Andres-Alonso et al., 2019 ; Kononenko et al., 2017 ), to pathogenesis of neurodegenerative disorders ( Moreau et al., 2014 ; Nixon, 2013 ; Ravikumar et al., 2010 ; Sarkar et al., 2007 ; Stavoe and Holzbaur, 2019 ). The importance of the autophagy system in the brain is emphasized by the fact that knockout of core ATG proteins, such as autophagy-related protein 5 (ATG5) or ATG7, induces accumulation of non-degraded protein aggregates, neurodegeneration, and neuronal cell death in mice ( Hara et al., 2006 ; Komatsu et al., 2006 , 2007 ).…”

The nuclear lamina is a hub for the nuclear function of Jacob

“…Proteins were bacterially produced and purified as previously described [ 31 ]. In brief, E. coli SHuffle (C3026) cells were transformed with either pMAL or LaminB1(PMXB10) vectors and E. coli ExpressLysY/Iq cells were transformed with CRM1 (PMXB10) vector.…”

Autophagy and the endolysosomal system in presynaptic function

“…Multiple motor adaptors for the axonal transport of endosomes have been described and their mechanism of cargo interaction is generally well described [97][98][99][100][101]. Interestingly, the function of these motor adaptors is not restricted to the transport of endosomes but they are also essential for the transport of autophagosomes and autophagy-derived vesicles [100,[102][103][104][105][106][107], suggesting a common mechanism for retrograde transport of both organelles. How autophagosomes acquire these motors is not well understood and available evidence indicate that autophagosomes fuse to LEs to recruit dynein for retrograde transport (Fig.…”