Figure 1.

Monomeric and dimeric α-synuclein produce distinct effects on clathrin- mediated synaptic vesicle (SV) endocytosis.

(A) Model showing SV recycling and the role for clathrin-mediated endocytosis. For simplicity, other membrane recycling pathways (e.g., bulk endocytosis) are not shown. Under physiological conditions, α-synuclein localizes to the SV cluster and regulates exocytosis and endocytosis, though the exact mechanisms are unclear. Following SV exocytosis and neurotransmitter release, the vesicle membrane is recycled via clathrin-mediated endocytosis. The basic stages of clathrin-mediated endocytosis are: initiation of clathrin coat formation; maturation of the coated pit; vesicle fission; and clathrin uncoating. Once uncoated, the vesicle is returned to the cluster where it can be re-used in another bout of neurotransmitter release. (B) Acute introduction of monomeric α-synuclein to synapses results in a loss of SVs, extension of the plasma membrane, and build up clathrin intermediates, predominantly CCVs. Thus, monomeric α-synuclein inhibits SV recycling at least in part by impairing clathrin uncoating. (C) In contrast, introduction dimeric α-synuclein increases the numbers of CCPs that are still connected to the plasma membrane, indicating a defect in vesicle fission. Thus, α-synuclein monomers and dimers produce distinct effects on clathrin-mediated SV recycling.