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. 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. In cortical and hippocampal neurons BDNF initiates signalling by binding to its receptor TrkB in distal neurites 17. In spite of these findings the physiological function of neuronal autophagosomes and their role in promoting neuronal survival and counteracting neurodegeneration remains incompletely understood.Ī crucial pathway that promotes neuronal survival, protects from neurodegeneration and promotes neuronal complexity 17 is the brain-derived neurotrophic factor (BDNF) signalling pathway. Accumulation of autophagosomes is a hallmark of neurodegenerative disorders including Alzheimer’s and Huntington’s disease, or amyotrophic lateral sclerosis 11, 12, 13, 14, while knockout (KO) of key autophagy proteins in mice causes neurodegeneration 15, 16. In the brain, autophagosomes form locally in distal axons and are trafficked retrogradely 10 to eventually fuse with lysosomes enriched in the neuronal soma. In addition to the cytoprotective function of autophagy under conditions of starvation 7, recent data support additional roles of autophagy, for example, in maintenance of stemness 8 or FGF signalling to mediate bone growth during development 9. Autophagosome formation requires an E3-like complex comprising ATG5 that catalyses lipid conjugation of microtubule-associated protein 1 light chain 3 (LC3) (ref. These undergo subsequent maturation steps, in particular fusion with late endosomes, to become late-stage autophagosomes also called amphisomes 4 before being delivered to lysosomes by dynein-mediated retrograde transport 5, 6. During autophagy portions of the cytoplasm are sequestered within double- or multimembraned vesicles termed autophagosomes. 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.Īutophagy is an evolutionary conserved process that serves to provide nutrients during starvation and to eliminate defective proteins and organelles 1, 2 such as mitochondria and the endoplasmic reticulum via lysosomal degradation 3. p150 Glued/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. 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. Although defective neuronal autophagy is associated with neurodegeneration, the function of neuronal autophagosomes remains incompletely understood. In neurons, autophagosomes form in distal axons and are trafficked retrogradely to fuse with lysosomes in the soma. Autophagosomes primarily mediate turnover of cytoplasmic proteins or organelles to provide nutrients and eliminate damaged proteins.
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