H2020Individual fellowship2015–2017

Syncrip_2014 · The molecular basis of learning and memory: uncovering the link between neuronal activation and localized translation at the synapse.

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration: 2015-09-01 → 2017-08-31
EU contribution: €183,455
Participants: 1
Scheme: MSCA-IF-EF-ST

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Results in brief

The molecular basis of learning and memory: uncovering the link between neuronal activation and localized translation at the synapse.

• What is the problem/issue being addressed? During learning, specific neuronal connections are strengthened and weakened to create long-term memory. This requires local regulation of the availability of proteins at the synapse, at a large distance from the cell body, in response to neuronal activity. It is generally recognised that such synaptic plasticity can be achieved through the regulation of translation of localized mRNAs at or near synapses, yet the molecular basis by which this process occurs is still largely unknown in any system. This project addressed this deficiency by studying a regulatory component involved in activity dependent synaptic plasticity. • Why is it important for society? Activity-dependent plasticity is the biological basis for learning and memory formation. Many neurodegenerative diseases impact upon memory recall and impair new memories from being stored. Advances made to explain the molecular characterization of this process will be beneficial designing treatments to avert these symptoms during the progression of disease. • What are the overall objectives? My project was to investigate the molecular mechanisms that regulate localised translation at the synapse in response to neuronal stimulation: a fundamentally important mechanism for regulating synaptic plasticity. We previously identified Syncrip, a conserved RNA binding protein, as an important factor for synaptic function. The aim was to: 1) Investigate how neuronal stimulation regulates Syncrip. 2) Understand how Syncrip controls the localized translation of its target mRNAs at the synapse

Data: CORDIS, © European Union

Project objective

During learning specific neuronal connections are strengthened and weakened to create long-term memory. This requires local regulation of the availability of proteins at the synapse, at a large distance from the cell body, in response to neuronal activity. It is generally recognized that such synaptic plasticity can be achieved through the regulation of translation of localized mRNAs at or near the synapses. Despite the importance of this mechanism in memory and our understanding of neurodegenerative diseases, the molecular basis by which neuronal activation regulates localised translation is still largely unknown in any system. I propose to address this deficiency by discovering the key regulatory pathway in activity dependent synaptic plasticity in the Drosophila third instar motorneuron synapse, a well established model for generalised synaptic function. My proposal is built on extremely promising unpublished observations showing that a highly conserved mRNA binding protein, Syncrip (Syp) regulates the localized translation of key synaptic mRNAs, such as the conserved scaffolding molecule Discs large, at the motorneuron synapse, in response to neuronal stimulation. Preliminary data from the lab suggests that Syp is post-translationally modified by Calcium/calmodulin-dependent protein kinase II (CaMKII), a well-known kinase that plays essential and conserved roles in memory. I propose to test the hypothesis that binding of Syp to its mRNA targets is regulated by phosphorylation by CamKII. I will test whether Syp is phosphorylated at CamKII consensus sites located in its mRNA binding domains, which have been modelled on the human structure. We will use mass spectrometry to identify these phosphorylation sites and characterise phosphorylation mutants of Syp generated by CRISPR. I also aim to discover the molecular mechanism by which Syncrip regulates the translation of its targets.

Original text from CORDIS.

Participants

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordCoordinatorUnited Kingdom

Syncrip_2014 · The molecular basis of learning and memory: uncovering the link between neuronal activation and localized translation at the synapse.

Results in brief

The molecular basis of learning and memory: uncovering the link between neuronal activation and localized translation at the synapse.

Project objective

Participants

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