Biology subjects

Coba, M. P.

Publications and source records attributed to Coba, M. P..

4 recordsLinked to original sources

bioRxiv2026

Vascular and synaptic proteomes reveal blood-brain barrier disruption and postsynaptic remodeling in human temporal lobe epilepsy

Blood-brain barrier (BBB) dysfunction and mesial temporal lobe epilepsy (MTLE) are considered to be engaged in a pathological feedback loop, with the consequent worsening of both conditions. However, the molecular landscape of the disruptions at the synapse and the blood-brain barrier during MTLE remains poorly characterized. Here, we perform quantitative proteomics on paired brain microvessel and vessel-depleted postsynaptic density (PSD) enriched fractions isolated from the epileptic hippocampus and ipsilateral temporal pole of patients with drug-resistant MTLE. The microvessel fraction (1,541 proteins; 439 differentially expressed proteins (DEPs)) reveals loss of tight-junction and endothelial adhesion proteins together with pericyte markers, concurrent with a significant increase of fibrinogen, plasminogen, complement C3, GFAP, and enrichment for complement and coagulation cascades. The PSD enriched fraction (7,450 proteins; 1,881 DEPs) shows the consequences of BBB leakage with an increase of protein infiltration, alongside inflammatory and extracellular-matrix proteins, together with disruption of the pre- and postsynaptic signaling machinery and loss of GABAergic interneurons. Cross-referencing healthy-brain expression confirms that the dysregulation of the processes reflects disease-associated changes rather than regional differences. Immunohistochemistry confirms microvascular remodeling, pericyte loss, parenchymal fibrinogen extravasation, microglial activation and presynaptic marker depletion in the epileptic hippocampus. Ligand-receptor mapping reveals dysregulation of the neurovascular ECM-adhesion interface, with upregulated parenchymal ECM ligands and downregulated vascular integrin receptors. Network-proximity analyses nominate candidate disease-modifying compounds for reversing the combined vascular and synaptic MTLE signature. Together, these findings establish a molecular map of vascular and synaptic dysfunction in human MTLE.

neuroscience↗

bioRxiv2026

Disruption of the SYNGAP1 PDZ ligand motif accelerates differentiation of human iPSC-derived GABAergic neurons

SYNGAP1 haploinsufficiency is a leading genetic cause of neurodevelopmental disorders (NDD), including intellectual disability and epileptic encephalopathy. While most studies on SYNGAP1 function have focused on glutamatergic neurons, its role in GABAergic neurons and during early neuronal development is unclear. Using human iPSC-derived GABAergic neurons, we demonstrate that SYNGAP1 haploinsufficiency accelerates neuronal maturation, characterized by increased dendritic length, synaptic density, and maturation of synaptic structures. Disruption of the isoform-specific SYNGAP1 PDZ binding motif reproduces these phenotypes, highlighting the critical role of PDZ-mediated interactions in regulating GABAergic neuronal differentiation. Proteomic and phosphoproteomic analyses reveal significant dysregulation of synaptic proteins, RNA processing, and transcriptional control, with a significant increase in postsynaptic density proteins content. RNA-seq analysis suggest that the acceleration in neuronal differentiation starts few hours after neuronal induction setting a path to a faster neuronal and synapse maturation. These findings establish that SYNGAP1 acts as a key regulator of neuronal differentiation across both excitatory and inhibitory neurons. Our work underscores the importance of the SYNGAP1 PDZ ligand motif for normal neuronal development and suggests translational strategies targeting SYNGAP1 alpha1 isoform levels to mitigate SYNGAP1-related NDD.

neuroscience↗

bioRxiv2025

Multiomic profiling reveals pericyte and smooth muscle cell contributions to CADASIL pathology in cell-specific Notch3 mutant mice

Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial SVD. CADASIL is caused by dominant missense mutations in Notch3, a receptor expressed in mural cells, including smooth muscle cells (SMCs) and pericytes. However, the cell-type specific contributions driving the CADASIL pathology remain unknown due to lack of animal models. Here, we generated two conditional knock-in mouse models carrying the CADASIL-causing Notch3R170C mutation selectively in SMC and brain pericytes. Both Notch3R170Cmodels showed perivascular accumulation of the NOTCH3 extracellular domain, yet developed distinct neurovascular changes depending on the affected cell type. Pericyte-specific Notch3R170C mice displayed pronounced region-selective microglial activation and vascular changes, whereas SMC-specific Notch3R170C mice showed localized perivascular gliosis with minimal vascular remodeling. Proteomic profiling of isolated brain vessels revealed largely unique cell-specific responses. Pericytes Notch3R170C expression dysregulated metabolic pathways, whereas SMC Notch3R170C expression induced immune signaling related pathways. Integration with single-cell RNA-seq data revealed that many of the proteomic and phosphoproteomic shifts might also include brain endothelial cells, including metabolic changes in the presence of pericyte Notch3R170C and inflammatory signaling in the presence of SMC-Notch3R170C. Together, these findings define mural cell-specific mechanisms that contribute to the CADASIL-associated vascular pathology.

neuroscience↗

bioRxiv2020

Splicing of the SynGAP Carboxyl-Terminus Enables Isoform-Specific Tuning of NMDA Receptor Signaling Linked to Cognitive Function

SynGAP-1 is a splice variant of the neurodevelopmental disorder risk gene, SYNGAP1/Syngap1. 1 encodes the C-terminal PDZ binding motif (PBM) that promotes liquid-liquid phase separation, a candidate process for postsynaptic density organization within excitatory synapses. However, it remains unknown how the endogenous SynGAP PBM regulates synapse properties and related cognitive functions. We found that a major PBM function in mice is to limit the mobility of SynGAP-1 in response to NMDA receptor activation. Genetic disruption of the PBM increased SynGAP-1 mobility to levels consistent with other non-PBM-containing C-terminal isoforms. This resulted in a lowering of the threshold for NMDA receptor-dependent signaling required for plasticity, leading to aberrant strengthening of excitatory synapses in spontaneously active neurons. PBM-deficient animals also exhibited a lower seizure threshold, disrupted LTP, and impaired cognition. Thus, the PBM enables isoform-specific SynGAP gating of NMDA receptor function, a mechanism linking synaptic signaling dynamics to network excitability and cognition.

neuroscience↗