Degradative pathways and suggested presynaptic cargos
Synaptic proteins and organelles, such as SVs and mitochondria, can be locally removed via alternative degradative routes. The proteasome removes predominantly cytosolic proteins, including active zone proteins RIM1 and Munc13. ESCRT-dependent endolysosomal sorting is thought to be required for the degradation of a subset of membrane proteins, for instance, SV proteins VAMP2 and SV2. Both proteins and organelles can be sequestered by a double-membrane structure called a phagophore, which then closes to form an autophagosome that eventually fuses with somatic lysosomes for degradation. Ubiquitination is a common signal for degradation in all of these major protein degradation pathways. Therefore, ubiquitin-ligases (E3) and deubiquitinating enzymes could play important roles in maintaining a healthy presynapse. The six E3 ligases indicated here either have known, mammalian, presynaptic targets (Nedd4, Scrapper, Fbxo45, Staring) or are locally regulated by presynaptic proteins (Siah1, Parkin); EE, early endosome; SV, synaptic vesicle; MVB, multivesicular body.