FIGURE 1.
PD-linked and SVE-associated genes in synaptic vesicle recycling. Schematic representation of a presynaptic terminal showing the roles of PD-linked genes (orange) and SVE-associated genes (blue) in synaptic vesicle recycling. It shows the neurotransmitter release process, clathrin-mediated endocytosis, ultrafast endocytosis, and other processes in which PD genes are involved. (1) Neurotransmitter releasing. Synaptic vesicles from the reserve pool or derived from the uncoating process are loaded with neurotransmitters. The vesicles move toward the active zone and then fuse to the plasma membrane in the presence of synaptic proteins including α-syn. Neurotransmitters are released into the synaptic cleft. (2) Clathrin-mediated endocytosis. This process is initiated by the coating of the plasma membrane by clathrin. The coated membrane is curved via the activity of AMPH1. Then endophilin mediates the invagination of the clathrin-coated plasma membrane. Endophilin A1 recruits dynamin to the neck of the clathrin-coated vesicles (CCVs). Endophilin A1 contains several SH3 domains and interacts with SYNJ1 and/or Parkin. Once recruited, SYNJ1 dephosphorylates PI(4,5P)2 into PI, shedding clathrin and its adaptor from the bilayer. LRRK2 phosphorylates endophilin, leading to dissociation of the later from CCVs. The removal of the clathrin coat is mediated by auxilin. Finally, the uncoated endocytic vesicles move into the reserve pool, or directly undergo loading and releasing process. (3) Ultrafast endocytosis. During this type of endocytosis, AMPH1 and endophilin A1 are recruited to the plasma membrane, and regulate the curvature of the emerging vesicle. Dynamin then constricts the neck and mediates synaptic vesicle fission from the plasma membrane. The large endocytic vesicles cluster and fuse to form synaptic endosomes. The synaptic endosomes are further coated by clathrin to generate CCVs, which undergo clathrin-uncoating and generate endocytic vesicles. (4) Other processes mediated by PD-related genes. PTEN is a lipid phosphatase that is inhibited by DJ-1. PTEN increases the level of PINK1 in the mitochondrial. PINK1 is released by the mitochondria and triggers neuronal differentiation. The PTEN-Parkin axis is necessary for proper mitochondrial function. This guarantees ATP synthesis and is necessary for most processes, such as vesicle fusion and the mobilization of the vesicles in the reserve pool during synaptic vesicle recycling.PI(4,5)P2, phosphatidylinositol 4,5-bisphosphate; PI, phosphatidylinositol; α-syn, alpha-synuclein; AMPH1, amphiphysin 1; SYNJ1, synaptojanin 1; LRRK2, leucine-rich repeat serine/threonine protein kinase 2; PTEN, phosphatase and tensin homolog; PINK1, PTEN induced putative kinase 1; DJ-1, Parkinson’s disease protein 7; ATP, adenosine triphosphate.