Proteomy naczyniowe i synaptyczne ujawniają uszkodzenie bariery krew-mózg i przebudowę synaps w ludzkiej padaczce płata skroniowego
Vascular and synaptic proteomes reveal blood-brain barrier disruption and postsynaptic remodeling in human temporal lobe epilepsy
W skrócie
[Preprint - wstępne wyniki] Badanie wykazało, że u pacjentów z opornością na leki postaci padaczki płata skroniowego dochodzi do uszkodzenia bariery krew-mózg oraz zaburzeń w synapsach mózgowych. Naukowcy znaleźli ubytek białek szczelujących naczynia, napływ białków zapalnych i zwiększoną aktywność komórek obronne, co prowadzi do zaburzeń przekazywania sygnałów między neuronami. Wyniki mogą pomóc w opracowaniu nowych leków wspomagających przywrócenie prawidłowego funkcjonowania zarówno naczyń mózgowych, jak i połączeń między neuronami.
Oryginalny abstract (angielski)
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.