Project description
Unveiling the architecture of synaptic proteins in health and disease
Transmission of neuronal information in the brain occurs through specialised structures known as synapses. Synapses contain more than 2 000 distinct proteins, and their spatial organisation, architecture and interaction network remain poorly mapped. Scientists of the EU-funded SynLink initiative aim to develop a cross-linking mass spectrometry pipeline for the structural analysis of the synaptic proteome. The SynLink approach will contribute to the identification of synaptic network rearrangements and alterations that take place during learning and memory. Importantly, it can be used to study synaptic dysfunction, which underlies various neurological and psychiatric disorders.
Objective
Brain function crucially depends on chemical neurotransmission at synapses, while, conversely, synaptic dysfunction underlies neurological and psychiatric disorders. Synapses are composed of more than 2,000 distinct proteins, spatially organized into specialized molecular machineries. During decades of efforts, researchers have acquired a wealth of knowledge on individual key components of the synapse. However, the overall picture of the spatial arrangement, molecular architecture and interaction network of the synaptic proteome remains largely uncharted. Furthermore, innovative methods that allow system-wide profiling of these organizational aspects of synaptic proteins are in great demand.
I propose to develop a highly sensitive cross-linking mass spectrometry (XL-MS) pipeline to analyze structural and organizational features of the synaptic proteome at an unprecedented depth and comprehensiveness. In parallel, I also plan to establish quantitative XL-MS strategies to reveal global network rearrangements and complex-specific alterations during long-term potentiation, which arguably is the most attractive cellular model for learning and memory. Importantly, it is foreseeable that numerous novel insights can be discovered, for which I will use complementary approaches and tools, such as biochemistry, super-resolution imaging, structural modelling and network analysis to validate and interrogate their molecular details and network principles. These studies will yield groundbreaking insights into the molecular architecture of the synapse and thereby fill a crucial knowledge gap in neuroscience. Furthermore, they will provide a framework to gain a deeper understanding of the dynamic regulation in synaptic plasticity and synaptic dysfunction in neurological disorders.
Fields of science
- natural sciencesbiological sciencesneurobiology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesclinical medicinepsychiatry
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
12489 Berlin
Germany