Communication between nerve cells takes place by the release of neurotransmitters at synapses. Signaling can be extremely rapid - transmitting information via hundreds of action potentials per second. It is not possible to synthesize new synaptic vesicles at this pace, so rapid recycling is essential. Although endocytosis at the synapse is at the core of synaptic transmission, the debate about the mechanism has continued for over 40 years without resolution. We recently discovered that synaptic vesicle endocytosis at synapses in the nematode C. elegans and mouse hippocampal neurons occurs as rapidly as 50 ms rather than 20 seconds, as determined previously. Our preliminary results suggest that this process requires polymerized actin and myosin-II. Each one of our aims will incorporate pharmacological studies in hippocampal neurons and genetic studies in C. elegans on particular molecular targets.
Aim 1. The role for actin in membrane invagination could be via active polymerization, stable actin filaments, branched actin, or stable cortical actin plates.
Aim 2. Myosin-II function in ultrafast endocytosis will be tested in hippocampal neurons and in C. elegans.
Aim 3. The forming / diaphanous proteins polymerize actin filaments and function with myosin-II.
Aim 4. Rho activates Formin directly, and Rho activates Myosin-II via the kinase ROCK.
Aim 5. It is not known whether ultrafast endocytosis only retrieves membrane or whether it also retrieves synaptic vesicle proteins from the surface. We will tag the lumenal side of synaptic vesicle proteins and determine whether they are incorporated into endocytic vesicles. There is growing evidence that understanding endocytosis will have direct impact on applied health research, since defects in endocytosis may play causative roles in neuronal diseases, including Huntington's Disease, the ataxias, Parkinson's Disease, Hermansky-Pudlack syndrome, and Alzheimer's Disease. It is our hope that understanding the process of endocytosis may lead to drug therapies for these diseases in the future. Finally, we are developing innovative new techniques that will aid other researchers by bringing new weapons to these and other problems.
Nerve cells communicate via synaptic transmission, but defects in this process can lead to diseases of the nervous system, such as Parkinson's Disease and Alzheimer's Disease. By studying the basic processes of recycling at neuronal synapses, we hope to understand the causes of neurodegenerative diseases as well as develop novel therapies.
| Watanabe, Shigeki; Mamer, Lauren Elizabeth; Raychaudhuri, Sumana et al. (2018) Synaptojanin and Endophilin Mediate Neck Formation during Ultrafast Endocytosis. Neuron 98:1184-1197.e6 |
| Kurshan, Peri T; Merrill, Sean A; Dong, Yongming et al. (2018) ?-Neurexin and Frizzled Mediate Parallel Synapse Assembly Pathways Antagonized by Receptor Endocytosis. Neuron 100:150-166.e4 |
| Topalidou, Irini; Chen, Pin-An; Cooper, Kirsten et al. (2017) The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans. Genetics 206:265-282 |
| Chen, Bojun; Liu, Ping; Hujber, Edward J et al. (2017) AIP limits neurotransmitter release by inhibiting calcium bursts from the ryanodine receptor. Nat Commun 8:1380 |
| German, Christopher L; Gudheti, Manasa V; Fleckenstein, Annette E et al. (2017) Brain Slice Staining and Preparation for Three-Dimensional Super-Resolution Microscopy. Methods Mol Biol 1663:153-162 |
| Jang, SoRi; Nelson, Jessica C; Bend, Eric G et al. (2016) Glycolytic Enzymes Localize to Synapses under Energy Stress to Support Synaptic Function. Neuron 90:278-91 |
| Bend, Eric G; Si, Yue; Stevenson, David A et al. (2016) NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations. Neurology 87:1131-9 |
| Li, Pengpeng; Merrill, Sean A; Jorgensen, Erik M et al. (2016) Two Clathrin Adaptor Protein Complexes Instruct Axon-Dendrite Polarity. Neuron 90:564-80 |
| Yogev, Shaul; Cooper, Roshni; Fetter, Richard et al. (2016) Microtubule Organization Determines Axonal Transport Dynamics. Neuron 92:449-460 |
| Geisler, Florian; Gerhardus, Harald; Carberry, Katrin et al. (2016) A novel function for the MAP kinase SMA-5 in intestinal tube stability. Mol Biol Cell 27:3855-3868 |
Showing the most recent 10 out of 71 publications
