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Sorting out the synapse: the role of intracellular trafficking in NMDA receptor homeostasis (2016–2018)

Abstract:
Membrane trafficking is essential for neuronal function, as cell surface receptors and ion channels must be very tightly regulated for proper synaptic transmission. We will examine the role of membrane trafficking in the control of N-methyl-D-aspartate receptors (NMDARs), which are critical mediators of synaptic plasticity, and important targets for the treatment of neurodegenerative and neuropsychiatric disorders. In particular we will define the mechanism of NMDAR transport governed by a highly conserved protein complex called sorting nexin 27 (SNX27)-retromer. This complex is a central mediator of receptor recycling from intracellular endocytic compartments, preventing degradation in late endosomes and lysosomes. Like the NMDARs themselves, SNX27-retromer is an emerging target in neurodegenerative disorders including Parkinson¿¿¿s disease, Alzheimer¿¿¿s disease, and Down Syndrome. Our hypothesis is that SNX27-retromer regulates the post-synaptic cell surface distribution of the NMDARs required for synaptic transmission. We find that SNX27-retromer binds to short sequences called PDZ binding motifs (PDZbms) in the NMDARs, and most intriguingly we have uncovered a novel role for phosphorylation of the NMDARs in promoting SNX27-retromer interactions, which may have implications for activity-dependent trafficking of NMDARs during synaptic potentiation. Our goal is now to determine how the SNX27-retromer complex engages with the NMDARs through a combined structural and functional analysis of NMDAR trafficking in neurons, and to confirm the importance of NMDAR phosphoregulation for SNX27-retromer-mediated neuronal trafficking. We have assembled a team of scientists with expertise in structural and cellular studies of membrane trafficking and neuronal function, and this research will provide a fundamentally improved understanding of the interplay between SNX27-retromer and NMDARs, which are both targets for the treatment of neurodegenerati...
Grant type:
NHMRC Project Grant
Researchers:
Funded by:
National Health and Medical Research Council