NCAM-mediated ßI spectrin expression and NMDA receptor trafficking
Final Report Abstract
Synapses are specialized contacts between neurons, which are required to analyze and store information in the brain. Synapses are long lasting structures, which exist over prolonged periods of time. Our previous research showed that a molecule, called the Neural Cell Adhesion Molecule (NCAM), stabilize synapses. In this project we have analyzed how levels of this molecule are maintained in synapses, and whether NCAM also plays a role in the regulation of the protein composition of synapses by regulating transport of other synaptic proteins. We found that neurons continuously replenish the pool of synaptic NCAM molecules, and characterized the mechanisms promoting accumulation of NCAM at synapses. Since NCAM protein has a much shorter life time compared to the life time of a synapse, we propose that this is required to maintain synapses over prolonged periods of time. We have also demonstrated that NCAM regulates insertion and removal of the new membranes and proteins at synapses. We described structural proteins that NCAM binds to regulate transport of synaptic proteins, and identified enzymes which NCAM activates to influence the efficiency of the protein and membrane delivery. Mutations in NCAM lead to psychiatric disorders in humans, which are known to be linked to the malfunctioning of synapses in the brain. The results obtained in this work explain the molecular mechanisms of the disorders linked to mutations in NCAM, and can be used to design novel therapeutic drugs that will be used to treat such disorders. The results also improve our understanding of how the normal brain works.
Publications
- 2008. NCAM induces CaMKIIalpha-mediated RPTPalpha phosphorylation to enhance its catalytic activity and neurite outgrowth. J Cell Biol. 182:1185-200
Bodrikov V, Sytnyk V, Leshchyns'ka I, den Hertog J, Schachner M
- 2010. Clustering of the neural cell adhesion molecule (NCAM) at the neuronal cell surface induces caspase-8- and -3-dependent changes of the spectrin meshwork required for NCAM-mediated neurite outgrowth. J Biol Chem. 285:42046-57
Westphal D, Sytnyk V, Schachner M, Leshchyns'ka I
- 2011. Immobilized pool of NCAM180 in the postsynaptic membrane is homeostatically replenished by the flux of NCAM180 from extrasynaptic regions. J Biol Chem. 286:23397-406
Leshchyns'ka I, Tanaka MM, Schachner M, Sytnyk V
- 2011. NCAM/spectrin complex disassembly results in PSD perforation and postsynaptic endocytic zone formation. Cereb Cortex. 21:2217-32
Puchkov D, Leshchyns'ka I, Nikonenko AG, Schachner M, Sytnyk V
- 2011. The neural cell adhesion molecule promotes FGFR-dependent phosphorylation and membrane targeting of the exocyst complex to induce exocytosis in growth cones. J Neurosci. 31:3522-35
Chernyshova Y, Leshchyns'ka I, Hsu SC, Schachner M, Sytnyk V
