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.
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Coba MP, Pocklington AJ, Collins MO, Kopanitsa MV, Uren RT, Swamy S, Croning MD, Choudhary JS, Grant SG. Neurotransmitters drive combinatorial multistate postsynaptic density networks. Sci Signal. 2009; 2(68):ra19. View in: PubMed
Coba MP, Valor LM, Kopanitsa MV, Afinowi NO, Grant SG. 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
Cuthbert PC, Stanford LE, Coba MP, Ainge JA, Fink AE, Opazo P, Delgado JY, Komiyama NH, O'Dell TJ, Grant SG. 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
Collins MO, Yu L, Coba MP, Husi H, Campuzano I, Blackstock WP, Choudhary JS, Grant SG. Proteomic analysis of in vivo phosphorylated synaptic proteins. J Biol Chem. 2005 Feb 18; 280(7):5972-82. View in: PubMed