Synaptojanin 1 Mutation in Parkinson’s Disease Brings Further Insight into the Neuropathological Mechanisms

Figure 2

Synaptic vesicle recycling and PD genes. Schematic representation of a presynaptic terminal showing the PD genes (red boxes) and their role in synaptic vesicle recycling. (a) During endocytosis, invagination of the clathrin-coated membrane requires endophilin. Endophilin harbors several SH3 domains, which can interact with SYNJ1 PRD domain and/or parkin. (b) LRRK2 phosphorylates endophilin leading to dissociation of the later from clathrin-coated vesicles. (c) Once recruited to the coated vesicles through endophilin, SYNJ1 dephosphorylates PI4,5P into PI, shedding clathrin and its adaptor from the bilayer. (d) Uncoating of the vesicles also requires auxilin intervention and subsequent chaperoning of clathrin molecules. Then, the postendocytic vesicles can return to the reserve pool, where they undergo clustering, or return directly to the release site and enter in an exocytosis step. (e) Synaptic vesicles are docked and then fused to the membrane by means of a multiprotein complex including synaptobrevin and αSYN. (f) PTEN is a lipid phosphatase, which is inhibited by DJ-1, and can increase levels of the mitochondrial PINK1 protein. This pathway is involved in NMDA receptor signaling. (g) Proper mitochondrial functioning leads to ATP synthesis, necessary to mobilize the reserve pool of vesicles during synapse stimulation. PI4,5P: phosphatidylinositol 4,5-bisphosphates; PI: phosphatidylinositol; ATP: adenosine triphosphate; SYNJ1: synaptojanin 1; LRRK2: leucine-rich repeat serine/threonine-protein kinase 2; PTEN: phosphatase and tensin homologue; PINK1: PTEN induced putative kinase 1; DJ-1: Parkinson’s disease protein 7; αSYN: alpha-synuclein.