Description du projet
Révéler l’architecture des protéines synaptiques dans les états normaux et pathologiques
La transmission des informations neuronales dans le cerveau se fait au travers de structures dédiées appelées des synapses. Les synapses contiennent plus de 2 000 protéines distinctes, et leur organisation spatiale, leur architecture et leur réseau d’interactions sont encore mal cartographiés. Les chercheurs de l’initiative SynLink, financée par l’UE, veulent développer un pipeline de spectrométrie de masse à liaison croisée pour l’analyse structurelle du protéome synaptique. L’approche SynLink contribuera à identifier les réarrangements et les altérations du réseau synaptique qui se produisent au cours de l’apprentissage et de la formation de la mémoire. Surtout, elle pourra être utilisée pour étudier le dysfonctionnement synaptique à l’origine de différents troubles neurologiques et psychiatriques.
Objectif
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.
Champ scientifique
- natural sciencesbiological sciencesneurobiology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesclinical medicinepsychiatry
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
12489 Berlin
Allemagne