Project description
Nanoscale atlas of sub-synaptic protein architecture of the brain
Most brain disorders are associated with damage to synapse proteins. The single-synapse resolution map of brain protein composition shows unique spatio-temporal synapse distributions in the brain. Synapse proteins function in the context of multiprotein complexes and supercomplexes. The EU-funded SYNarch project aims to elucidate the sub-synaptic protein architecture and the spatio-temporal organisation of synapse diversity in health and disease. The researchers will employ a combination of biochemical, molecular imaging, ultrastructural and computational technologies to investigate spatial relationships and the number of complexes within individual synapses. The objective is to create a nanoscale atlas of the synaptome architecture of the brain and uncover how it is impacted in the schizophrenia mouse model.
Objective
Synapses play an essential role in all behaviours and damage to synapse proteins results in over a 130 brain disorders. The host Grant lab has developed methods for brain-wide mapping of protein composition at single-synapse resolution, uncovering unexpected diversity. The different synapse types show unique spatiotemporal distributions in the brain across the lifespan, which are altered in genetic models of autism and schizophrenia. Synapse proteins are assembled into multiprotein complexes and supercomplexes, but little is known about their composition and spatial organisation within individual synapses, particularly in the intact brain. In SYNarch I aim to understand this subsynaptic protein architecture, its contribution to the spatiotemporal organisation of synapse diversity, and alteration in disease. The work plan will deliver a depth of skill acquisition integrated across a range of cutting-edge biochemical, molecular imaging, ultrastructural and computational technologies. In WP1 I will optimise use of Förster resonance energy transfer (FRET) to probe the sub-10 nm spatial relationship and number of endogenously labelled PSD95 complexes within individual synapses, backed up by complementary super-resolution microscopy techniques (STORM, TIRF) and microfluidics analysis. In WP2, FRET will be integrated with synaptome mapping technology to deliver an atlas of nanoscale information on a brain-wide scale – the PSD nanoscale synaptome architecture (PNSA) of the mouse brain. In WP3 I will uncover how the PNSA is impacted in the Dlg2 schizophrenia mouse model. SYNarch will help to provide new molecular insight into brain function and dysfunction on an unprecedented scale.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
EH8 9YL Edinburgh
United Kingdom