We study membrane trafficking mechanisms in neurons, which control the proper formation and function of interneuronal contacts, synapses. Our current interest is in scaffolding molecules, which may simultaneously interact with effector proteins and signaling components in neurons. These scaffolds play an important role in coordination and targeting of the effector molecules in synapse formation during development and in adult synapses during neurotransmitter release.
Our recent experiments demonstrated that the endocytic scaffolding proteins, Eps15 and Intersectin/Dap160 link exo- and endocytosis in central synapses. These molecular scaffolds are accumulated in the synaptic vesicle pool at rest (Figure, red). Along with synaptic vesicle associated protein synapsin (Figure, green) they are involved in clustering of neurotransmitter-filled vesicles at the active zone. During synaptic activity vesicles fuse with the plasma membrane and release the neurotransmitter. The scaffolding complex Eps15-Intersectin/Dap160 targets endocytic effector proteins to the periactive zone and together they promote reformation of synaptic vesicles and proliferation of the actin cytomatrix (Figure, blue). During recovery, the scaffolding and endocytic effectors proteins relocate back to the vesicle cluster.
Mutations in scaffolding proteins have been implicated in various neurological diseases. They result in an abnormal synapse formation, and affect regeneration of axonal projections following CNS injury. Currently we are focused on elucidating putative molecular links between observed malfunctions in the interactions of these scaffolding proteins and onset of abnormal synapse formation and degeneration.
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