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Modelling Argonaute protein interactions as predictors of local protein translation during synaptic plasticity in neurons Supervisory team: Main supervisor: Dr Jonathan Hanley (University of Bristol) Second supervisor: Dr Lucia Marucci (University of Bristol) Collaborators: Dominic Alibhai (University of Bristol) Host institution: University of Bristol Project description: MicroRNAs (miRNAs) are small RNAs encoded in the genome that mediate post-transcriptional silencing of messenger RNA (mRNA) targets by associating with Argonaute proteins in the RNAinduced silencing complex (RISC). Neuronal-specific miRNAs drive neuronal development and have important roles in various brain disorders, such as Alzheimer’s, Parkinson’s, Autism Spectrum Disorders and others. Long-term synaptic plasticity underlies learning and memory and the tuning of neural circuitry. The major processes that underlie synaptic plasticity are the regulated trafficking of AMPA receptors to change the receptor complement at the synapse, and alterations in the morphology of dendritic spines, the structures that house the postsynaptic machinery. Evidence has recently emerged that several dendritic miRNAs modulate the local translation of proteins that control spine morphology or AMPAR trafficking and hence synaptic transmission. Argonaute associates with various proteins that are essential for, or modulate, translational repression, including GW182, Hsp90, Dicer, MOV10 and PICK1. Experimental data from our lab indicate that at least some of these interactions are regulated by the induction of Long-Term Depression (LTD), causing an increase in RISC activity, and hence providing a mechanism for increasing miRNA-mediated translational repression as a part of the expression of synaptic plasticity. We hypothesise that these dynamic interactions act in a concerted network to control the level of miRNA activity required for plasticity. The aim of this project is to investigate Argonaute protein-protein interactions in neurons in response to stimuli (eg. NMDA receptor activation) initially using biochemical methods, followed by advanced imaging techniques (FLIM/FRET) to analyse the temporal and spatial dynamics of protein interactions in neurons. miRNA activity will be quantified in individual neurons using fluorescent reporters under the control of 3’ untranslated regions taken from transcripts that are known targets of relevant miRNAs. Computational methods will also be employed to describe Argonaute-mediated regulation of gene expression. The acquired imaging/biochemical data will be combined with previous knowledge about miRNAs to develop a mathematical model, taking into account other molecular mechanisms that govern miRNA activity in response to the induction of synaptic plasticity. This project will be carried out under the expert supervision of Dr. Jonathan Hanley (neuronal cell biology) and Dr. Lucia Marucci (computational biology). The cell imaging and image analysis will be carried out in the state-of-the-art Wolfson Bioimaging Facility at the University of Bristol, with the expert assistance of their technical team.