Tackling the synaptopathy challenges - synaptic systems biology from molecules to networks (1/2)
The EuroSPIN consortium will pursue a multi-level systems biology approach to determine mechanistic relationships between mutations of synaptic proteins and neurological and psychiatric diseases, and to develop new diagnostic tools and therapies. Our concept covers all conceptual and methodological aspects of the FP7 call HEALTH-2009-2.2.1-1. It is based on the current knowledge of disease genes, which we will continuously extend with new human genetic, proteomics, and transcriptomics data, and complement with large-scale screens of mutant mice in order to identify and characterize disease-relevant mutations in synaptic proteins and corresponding mouse models. Our work plan is organized hierarchically according to increasing conceptual complexity (from proteins and their interactions via synaptic physiology and cell biology to systems neuroscience) and increasing complexity of experimental preparations and methodology (from chemical biology, proteomics, and interactomics via cell biological, imaging, and electrophysiological studies in cultures and slices to imaging and electrophysiological studies and behavioural studies in intact mice in vivo).
Our systems biology approach aims to understand the emergent properties of molecular networks and thus to explain how a single gene mutation can result in a particular phenotype. The data collected in the systems biology projects will be specifically analysed by overlaying the phenotypic and functional annotations onto molecular interaction networks. The use of proteomic strategies such as the TTAPT tag are also powerful ways of identifying sets of interacting proteins that are functionally important. Using proteomic profiling as a starting point, the binary interactions for the sets of proteins (and their domains) can then be mapped and a network generated. Partners in WP 1, WP 2, and WP 3 will systematically map out major complexes within the synaptic compartments using a combination of proteomic and bioinformatic strategies. These studies form an essential basis for all functional studies within the EuroSPIN consortium (WP 6, WP 7, WP 8, WP 9, WP 10), in the course of which the functions and disease-relevant dysfunctions of synaptopathy gene products will be studied at the synaptic, cellular, neuronal network, and behavioural levels.