Psychiatric diseases are complex developmental brain disorders, and human genomic studies have discovered many genes associated with disease susceptibility. For each of these disorders, synaptic proteins have been implicated, in particular those involved in synaptic plasticity and protein complexes associated to the post-synaptic density (PSD). Despite these discoveries, there has been a gap in understanding the underlying mechanisms that contribute to dysfunction in these disorders. Our long-term goal is to determine how psychiatric disorder candidate risk factors are functionally integrated at the synapse and how mutations affect their function, not individually, but in developmental signaling network.
A common regulatory mechanism to ensure that signaling components encounter their intracellular partners in the right place and time is the association of components in protein complexes. These protein interactions commonly use protein scaffolds with specialized protein-interaction modules (protein domains) as a key mechanism to achieve specificity. We consider that common and rare risk factors might affect overlapping signaling networks, integrating protein interactions through different cellular compartments and developmental stages.
We use a systems biology approach, combining state of the art proteomic assays to define protein complexes and post-translational modifications, together with mouse genetics, CRISPR technology, hiPSC derived neurons, computational biology, and synaptic physiology. These methods are used to integrate pyschiatric candidate risk factors into spatio-temporal signaling networks and determine how mutations associated to psychiatric disease regulate common signaling mechanisms. This will help us to define network maps that will allow us to stratify patients by their correspondent pathway signatures.
Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders. Nat Neurosci. 2017 Jun 26. View in: PubMed
Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse. Biol Psychiatry. 2016 Feb 26. View in: PubMed
Inference of domain-disease associations from domain-protein, protein-disease and disease-disease relationships. BMC Syst Biol. 2016; 10 Suppl 1:4. View in: PubMed
Long-term potentiation modulates synaptic phosphorylation networks and reshapes the structure of the postsynaptic interactome. Sci Signal. 2016; 9(440):rs8. View in: PubMed
The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells. Hum Mol Genet. 2013 Sep 15; 22(18):3749-60. View in: PubMed
TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. J Neurosci. 2012 Oct 3; 32(40):13987-99. View in: PubMed
Knockdown of mental disorder susceptibility genes disrupts neuronal network physiology in vitro. Mol Cell Neurosci. 2011 Jun; 47(2):93-9. View in: PubMed
Neurotransmitters drive combinatorial multistate postsynaptic density networks. Sci Signal. 2009; 2(68):ra19. View in: PubMed
Kinase networks integrate profiles of N-methyl-D-aspartate receptor-mediated gene expression in hippocampus. J Biol Chem. 2008 Dec 5; 283(49):34101-7. View in: PubMed
Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies. J Neurosci. 2007 Mar 7; 27(10):2673-82. View in: PubMed
Proteomic analysis of in vivo phosphorylated synaptic proteins. J Biol Chem. 2005 Feb 18; 280(7):5972-82. View in: PubMed