In the brain, information is transmitted, processed and memorised by neurons. To perform these functions, neurons must grow and form networks, in which individual neurons are connected to other neurons by specialised contacts called synapses. Neurons use synapses to communicate with other neurons and to process and store information.
The formation and maintenance of the neuronal networks and synapses is regulated by neural cell adhesion molecules expressed at the cell surface of neurons (see our review Sytnyk et al., Trends in Neurosciences, 2017). Our laboratory is interested in understanding the molecular and cellular mechanisms of this regulation and effects of its loss in disease. We also develop new technologies aimed at improving brain performance, enhancing learning and maintaining memory by modulating neural cell adhesion molecules.
My early work showed that neural cell adhesion molecules are the first proteins accumulating at nascent synaptic contacts between developing neurons and that these proteins stabilize the contacts and induce their transformation into mature synapses by capturing synaptic precursor organelles (Sytnyk et al., Journal of Cell Biology, 2002, featured on the cover page). We then found that neural cell adhesion molecules regulate the key processes involved in neuronal growth and synapse formation including intracellular signalling (Leshchyns’ka et al., Journal of Cell Biology, 2003; Bodrikov et al., Journal of Cell Biology, 2005, 2008; Sheng et al., Journal of Neuroscience, 2015), the assembly of the cytoskeleton (Puchkov et al., Cerebral Cortex, 2011; Li et al., Journal of Neuroscience, 2013) and polarised intracellular transport (Chernyshova et al., Journal of Neuroscience, 2011). We demonstrated that neural cell adhesion molecules modulate the assembly and maturation of the neurotransmitter-releasing machinery in axons (Leshchyns’ka et al., Neuron, 2006; Shetty et al., Journal of Neuroscience, 2013) and neurotransmitter-detecting machinery in dendrites of neurons (Sytnyk et al., Journal of Cell Biology, 2006; Sheng et al., Cerebral Cortex, 2019).
By using a novel technique for analysis of synapses in brains of individuals affected by neurodegenerative disorders, we demonstrated that the loss of synapses in Alzheimer’s disease is linked to the degradation of synaptic neural adhesion molecules (Leshchyns’ka et al., 2015; featured at the Medical News website and others, the front page of the UNSW website and in the Newsletter (Summer 2015/16) of the Australia and New Zealand Society for Cell and Developmental Biology). Currently, we analyse mechanisms of this loss and develop strategies that can be used to prevent it. We also investigate changes in neural cell adhesion in other neurodegenerative disorders such as Parkinson’s disease and motor neuron disease and use new transgenic mice to model abnormal function of neural cell adhesion molecules in these disorders and study its effects on the brain.
Sheng L, Leshchyns'ka I, Sytnyk V. (2019) Neural cell adhesion molecule 2 (NCAM2)-induced c-Src-dependent propagation of submembrane Ca2+ spikes along dendrites inhibits synapse maturation. Cerebral Cortex 29(4):1439-1459.
Sytnyk V, Leshchyns'ka I, Schachner M. (2017) Neural cell adhesion molecules of the immunoglobulin superfamily regulate synapse formation, maintenance, and function. Trends in Neurosciences. 40(5):295-308.
Leshchyns'ka I, Liew HT, Shepherd C, Halliday GM, Stevens CH, Ke YD, Ittner LM, Sytnyk V. (2015) Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease. Nature Communications. 6:8836. F1000Prime recommended.
Wobst H, Schmitz B, Schachner M, Diestel S, Leshchyns'ka I, Sytnyk V. (2015) Kinesin-1 promotes post-Golgi trafficking of NCAM140 and NCAM180 to the cell surface. J Cell Sci. 128(15):2816-29.
Sheng L, Leshchyns'ka I, Sytnyk V. (2015) Neural cell adhesion molecule 2 promotes the formation of filopodia and neurite branching by inducing submembrane increases in Ca2+ levels. Journal of Neuroscience. 35(4):1739-52.
Shetty A, Sytnyk V, Leshchyns'ka I, Puchkov D, Haucke V, Schachner M. (2013) The neural cell adhesion molecule promotes maturation of the presynaptic endocytotic machinery by switching synaptic vesicle recycling from adaptor protein 3 (AP-3)- to AP-2-dependent mechanisms. J Neurosci. 33(42):16828-45. F1000Prime recommended.
Li S, Leshchyns'ka I, Chernyshova Y, Schachner M, Sytnyk V. (2013) The neural cell adhesion molecule (NCAM) associates with and signals through p21-activated kinase 1 (Pak1). J Neurosci. 33(2):790-803.
Tian N, Leshchyns'ka I, Welch JH, Diakowski W, Yang H, Schachner M, Sytnyk V. (2012) Lipid raft-dependent endocytosis of close homolog of adhesion molecule L1 (CHL1) promotes neuritogenesis. J Biol Chem. 287(53):44447-63.
Chernyshova Y, Leshchyns'ka I, Hsu SC, 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(10):3522-35.
Leshchyns'ka I, Tanaka MM, Schachner M, Sytnyk V. (2011) Immobilized pool of NCAM180 in the postsynaptic membrane is homeostatically replenished by the flux of NCAM180 from extrasynaptic regions. J Biol Chem. 286(26):23397-406.
Puchkov D, Leshchyns'ka I, Nikonenko AG, Schachner M, Sytnyk V. (2011) NCAM/spectrin complex disassembly results in PSD perforation and postsynaptic endocytic zone formation. Cerebral Cortex. 21(10):2217-32.
Leshchyns'ka I, Sytnyk V, Richter M, Andreyeva A, Puchkov D, Schachner M. (2006) The adhesion molecule CHL1 regulates uncoating of clathrin-coated synaptic vesicles. Neuron. 52(6):1011-25. F1000Prime recommended.
Sytnyk V, Leshchyns'ka I, Nikonenko AG, Schachner M. (2006) NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex. J Cell Biol. 174(7):1071-85.
Sytnyk V, Leshchyns'ka I, Delling M, Dityateva G, Dityatev A, Schachner M. (2002) Neural cell adhesion molecule promotes accumulation of TGN organelles at sites of neuron-to-neuron contacts. J Cell Biol. 159(4):649-61. F1000Prime recommended.