Abstract
Autophagosomes primarily mediate turnover of cytoplasmic proteins or organelles to provide nutrients and eliminate damaged proteins. In neurons, autophagosomes form in distal axons and are trafficked retrogradely to fuse with lysosomes in the soma. Although defective neuronal autophagy is associated with neurodegeneration, the function of neuronal autophagosomes remains incompletely understood. We show that in neurons, autophagosomes promote neuronal complexity and prevent neurodegeneration in vivo via retrograde transport of brain-derived neurotrophic factor (BDNF)-activated TrkB receptors. p150Glued/dynactin-dependent transport of TrkB-containing autophagosomes requires their association with the endocytic adaptor AP-2, an essential protein complex previously thought to function exclusively in clathrin-mediated endocytosis. These data highlight a novel non-canonical function of AP-2 in retrograde transport of BDNF/TrkB-containing autophagosomes in neurons and reveal a causative link between autophagy and BDNF/TrkB signalling.
Highlights
Autophagosomes primarily mediate turnover of cytoplasmic proteins or organelles to provide nutrients and eliminate damaged proteins
Partial co-localization of endogenous AP-2 with light chain 3 (LC3) in neuronal processes was further confirmed by dual-colour time-gated stimulated emission depletion microscopy (STED) analysis of neurons treated with the vATPase inhibitor folimycin, a lysosomotropic agent, which prevents autophagosome, and, LC3b degradation via lysosomal proteolysis, and immunostained for AP-2a and LC3b (Fig. 1h,i, Supplementary Fig. 1j,k)
These data suggest that retrograde co-trafficking of AP-2 on autophagosomes may reflect a novel non-canonical function of AP-2 in autophagosome transport in primary neurons that likely is independent of its established role in clathrin-mediated endocytosis as further discussed below
Summary
Autophagosomes primarily mediate turnover of cytoplasmic proteins or organelles to provide nutrients and eliminate damaged proteins. Activated BDNF/TrkB complexes are internalized predominantly via macropinocytosis mediated by EHD4/pincher into so-called ‘signalling endosomes’ that are refractory to lysosomal degradation to ensure persistent signalling[18] Consistent with this model, BDNF/TrkB have been shown to require retrograde axonal transport to promote neuronal branching and survival and to counteract neurodegeneration[19,20]. We demonstrate that TrkB-signalling endosomes are late-stage autophagosomes that undergo retrograde transport to the neuronal soma via their association with the adaptor AP-2, an essential[23] protein complex hitherto thought to function exclusively in clathrin-mediated endocytosis[24,25] and in the reformation of synaptic vesicles in the brain[26]. Identify a novel function of autophagy in BDNF/TrkB signalling during brain development mediated by a non-canonical role of the endocytic adaptor AP-2
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