Neurodevelopmental neurodegenerative and psychiatric disease are complex brain disorders, and a multitude of genes have been described to contribute to their pathology with different penetrance. Human genetic studies have discovered many genes associated with disease susceptibility that are usually described as risk factors. 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 cellular dysfunction in these disorders. Our long-term goal is to determine how candidate risk factors are functionally integrated and how mutations affect their function, not individually, but in developmental signaling networks.

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 cell types, 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, computational biology, synaptic physiology, CRISPR technology, and hiPSC derived cell types from patients with mutations associated to complex brain disorders. This will help us to define network maps that will allow us to stratify patients by their correspondent pathway signatures, their genotype-phenotype relationship, and their genetic background.


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