Abstract
The endolysosomal system is present in all cell types. Within these cells, it performs a series of essential roles, such as trafficking and sorting of membrane cargo, intracellular signaling, control of metabolism and degradation. A specific compartment within central neurons, called the presynapse, mediates inter-neuronal communication via the fusion of neurotransmitter-containing synaptic vesicles (SVs). The localized recycling of SVs and their organization into functional pools is widely assumed to be a discrete mechanism, that only intersects with the endolysosomal system at specific points. However, evidence is emerging that molecules essential for endolysosomal function also have key roles within the SV life cycle, suggesting that they form a continuum rather than being isolated processes. In this review, we summarize the evidence for key endolysosomal molecules in SV recycling and propose an alternative model for membrane trafficking at the presynapse. This includes the hypotheses that endolysosomal intermediates represent specific functional SV pools, that sorting of cargo to SVs is mediated via the endolysosomal system and that manipulation of this process can result in both plastic changes to neurotransmitter release and pathophysiology via neurodegeneration.
Highlights
Compartmentalization in eukaryotic cells enables efficient spatiotemporal control of multiple parallel cellular processes by concentrating the required factors in confined microenvironments that provide the best conditions for these processes to proceed
We propose an alternative interpretation of synaptic vesicles (SVs) recycling by proposing that the SV pool is an integral part of the endolysosomal system in neurons, with equivalents of EE, recycling endosome (RE), late endosome (LE), and lysosomes functioning in concert at the presynapse, and supporting synaptic transmission, but the overall health of the neuron
The ever-increasing subdivision of functional SV pools described above suggests that the presynapse harbors a collection of functionally diverse organelles with distinct molecular compositions, not all of which engage directly in neurotransmission
Summary
Compartmentalization in eukaryotic cells enables efficient spatiotemporal control of multiple parallel cellular processes by concentrating the required factors in confined microenvironments that provide the best conditions for these processes to proceed. Biochemical studies examining endosomes purified from AP1 (adaptor protein 1) σ knockout mice suggest that VPS34 is required for the maturation of LE and lysosomes (multivesicular bodies) in axons via a mechanism which involves sorting at presynaptic endosomes mediated by ADP-ribosylation factor GTPase activating protein 1 and Rab GDP/GTP exchange factor (Candiello et al, 2016) This implies that, in presynaptic terminals, PI3-kinase activity may be at the core of a mechanism operating at the presynaptic endosomes which coordinates both generation of functional SVs and degradative pathways. Molecules essential for RE function are required for optimal SV endocytosis and cargo trafficking at the presynapse This suggests that REs are fully integrated into the SV recycling system and even that some SVs that undergo spontaneous and evoked fusion may be considered as a type of REs. Molecular discrimination between LEs and lysosomes is challenging because of the absence of selective molecular markers between these organelles. This suggests that both SV recycling and autophagy pathways are intricately linked in terms of both function and molecular requirements
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