Fig. 1.

Overview of the two pathways that collect and deliver axonal cargo for degradation in lysosomes. Neurons pose a highly compartmentalized morphology endowed with a dendritic tree, the soma and a very long axon (in orange), and are decorated by many synaptic contacts (inset). Synapses are sites with high turnover rates and metabolic demands, where elements of autophagy, endolysosomal system and proteasomal-mediated degradation are present. Two main degradative pathways exist in axons that deliver cargo to lysosomes (described in the lower box) localized in the soma. In autophagy, autophagosome formation is initiated at distal axons at the phagophore assembly site (PAS). Cargo is sequestered by the phagophore which closes generating autophagosomes that are decorated by the autophagy adaptor LC3b-II. Autophagosomes are retrogradely transported in a dynein-dependent manner to the soma, where they fuse with degradative lysosomes generating autolysosomes. The endolysosomal pathway typically receives cargo from the plasma membrane by clathrin-mediated endocytosis and its fate is decided in early-endosomes (EE), organelles abundant in Rab5. Cargo is recycled back to the plasma membrane via recycling endosomes (RE) or is sent for degradation upon internalization into intraluminal vesicles by the ESCRT complex present in late endosomes (LE) and multivesicular bodies (MVB). EE matures into LE/MVB that are Rab7-positive. Cargo is then degraded in endolysosomes that originate from the fusion of LE/MVB with lysosomes. Amphisomes are generated upon the fusion of LE/MVB with autophagosomes and this is a necessary step for the acquisition of retrograde motors by autophagosomes. Ub ubiquitinated receptors