Marcelo Pablo Coba, PhD

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.

• Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders Cell Syst. 2025 Apr 16; 16(4):101204. . View in PubMed
• Human cerebellar organoids with functional Purkinje cellsCell Stem Cell. 2024 01 04; 31(1):39-51. e6. . View in PubMed
• Mutations in the postsynaptic density signaling hub TNIK disrupt PSD signaling in human models of neurodevelopmental disorders Front Mol Neurosci. 2024; 17:1359154. . View in PubMed
• Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis Nat Neurosci. 2023 Dec; 26(12):2090-2103. . View in PubMed
• Functional and phosphoproteomic analysis of ß-adrenergic receptor signaling at excitatory synapses in the CA1 region of the ventral hippocampus Sci Rep. 2023 05 09; 13(1):7493. . View in PubMed
• Transcriptional diversity in specific synaptic gene sets discriminates cortical neuronal identity Biol Direct. 2023 05 09; 18(1):22. . View in PubMed
• A “multi-omics” analysis of blood-brain barrier and synaptic dysfunction in APOE4 mice J Exp Med. 2022 11 07; 219(11). . View in PubMed
• Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection Elife. 2022 04 08; 11. . View in PubMed
• Mapping genomic loci implicates genes and synaptic biology in schizophrenia Nature. 2022 04; 604(7906):502-508. . View in PubMed
• Genome Sequencing Variations in the Octodon degus, an Unconventional Natural Model of Aging and Alzheimer’s Disease Front Aging Neurosci. 2022; 14:894994. . View in PubMed
• Endogenous Cell Type-Specific Disrupted in Schizophrenia 1 Interactomes Reveal Protein Networks Associated With Neurodevelopmental Disorders Biol Psychiatry. 2019 02 15; 85(4):305-316. . View in PubMed
• SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse Neuron. 2019; (103):1-18. . View in PubMed
• Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons Nat Med. 2018 03; 24(3):313-325. . View in PubMed
• Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability Sci Rep. 2018 02 02; 8(1):2281. . View in PubMed
• Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders Nat Neurosci. 2017 Aug; 20(8):1150-1161. . View in PubMed
• Synaptic GAP and GEF Complexes Cluster Proteins Essential for GTP Signaling Sci Rep. 2017 07 13; 7(1):5272. . View in PubMed
• Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse Biol Psychiatry. 2016 12 15; 80(12):933-942. . View in PubMed
• Long-term potentiation modulates synaptic phosphorylation networks and reshapes the structure of the postsynaptic interactome Sci Signal. 2016 08 09; 9(440):rs8. . View in PubMed
• TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function J Neurosci. 2012 Oct 03; 32(40):13987-99. . View in PubMed
• Neurotransmitters drive combinatorial multistate postsynaptic density networks Sci Signal. 2009 Apr 28; 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 05; 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 07; 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

• Berger, Theodore
• Levitt, Pat