Research Project: Nöronal Fonksiyon üzerindeki kardiyovasküler stres etkileri : Bilişsel bozukluğa hücre içi yollar (cardiostressci)
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Contributors
Funders
ID
TB.00575
Authors
Gürsoy, Attila
Faculty Member
Publications
Shared proteins and pathways of cardiovascular and cognitive diseases: relation to vascular cognitive impairment
(American Chemical Society, 2024) Gürsoy, Attila; Keskin, Özlem; Şenyüz, Simge; Zeylan, Melisa Ece; Picon-Pages, Pol; Garcia-Elias, Anna; Tajes, Marta; Munoz, Francisco J.; Oliva, Baldomero; Garcia-Ojalvo, Jordi; Barbu, Eduard; Vicente, Raul; Nattel, Stanley; Ois, Angel; Puig-Pijoan, Albert; Department of Computer Engineering; Department of Chemical and Biological Engineering; Yes; College of Engineering
One of the primary goals of systems medicine is the detection of putative proteins and pathways involved in disease progression and pathological phenotypes. Vascular cognitive impairment (VCI) is a heterogeneous condition manifesting as cognitive impairment resulting from vascular factors. The precise mechanisms underlying this relationship remain unclear, which poses challenges for experimental research. Here, we applied computational approaches like systems biology to unveil and select relevant proteins and pathways related to VCI by studying the crosstalk between cardiovascular and cognitive diseases. In addition, we specifically included signals related to oxidative stress, a common etiologic factor tightly linked to aging, a major determinant of VCI. Our results show that pathways associated with oxidative stress are quite relevant, as most of the prioritized vascular cognitive genes and proteins were enriched in these pathways. Our analysis provided a short list of proteins that could be contributing to VCI: DOLK, TSC1, ATP1A1, MAPK14, YWHAZ, CREB3, HSPB1, PRDX6, and LMNA. Moreover, our experimental results suggest a high implication of glycative stress, generating oxidative processes and post-translational protein modifications through advanced glycation end-products (AGEs). We propose that these products interact with their specific receptors (RAGE) and Notch signaling to contribute to the etiology of VCI.
Oxidative stress-driven transcriptomic remodeling in human astrocytes reveals network signatures associated with neurodegenerative and cardiovascular processes
(Elsevier, 2026) Zeylan, Melisa Ece; Şenyüz, Simge; Keskin, Özlem; Gürsoy, Attila; Zeylan, Melisa Ece; Bota, Patricia M.; Picon-Pages, Pol; Fanlo-Ucar, Hugo; Almabhouh, Saja; Bagudanch, Oriol; Gohl, Patrick; Molina-Fernandez, Ruben; Fernandez-Fuentes, Narcis; Barbu, Eduard; Vicente, Raul; Nattel, Stanley; Ois, Angel; Puig-Pijoan, Albert; Garcia-Ojalvo, Jordi; Munoz, Francisco J.; Oliva, Baldomero; Graduate School of Sciences and Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Yes; Şenyüz, Simge; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING; College of Engineering
Astrocytes are central to brain homeostasis, supporting neuronal metabolism, synaptic activity, and the blood-brain barrier. With aging, these glial cells undergo molecular and functional changes that weaken support functions and promote neuroinflammation, contributing to neurodegeneration. Yet the systems-level mechanisms by which astrocytes respond to aging-related stressors remain poorly defined in human models. Because aging also heightens risk for cardiovascular disease, cognitive impairment, type 2 diabetes, and systemic inflammation, clarifying shared astrocytic pathways is critical for understanding brain-body crosstalk. Using an in vitro human astrocyte model exposed to sublethal oxidative stress (10 mu M H2O2) as a proxy for age-related cellular stress, we profiled transcriptomic changes and identified differentially expressed genes across antioxidant defenses, proteostasis, transcriptional regulation, vesicular trafficking, and inflammatory signaling. We then performed network-prioritization analyses on a curated human protein-protein interactome: one seeded with the astrocyte oxidative stress responsive genes and six with phenotype-associated gene sets (Alzheimer's disease, cardiovascular disease, cognitive impairment, type 2 diabetes, oxidative stress, and inflammation). Intersecting the top 5 % scoring genes from each run yielded a 127-gene core shared across all seven, enriched for proteostasis, DNA repair, mitochondrial regulation, and telomere and nuclear envelope maintenance. Structure-guided analyses highlighted vulnerable interfaces, including lamin A/C-lamin B1, alpha-actinin-filamins, 14-3-3 dimers, and aminoacyl-tRNA synthetase assemblies, where pathogenic variants are predicted to destabilize or aberrantly stabilize protein interactions. Structure-based interface predictions also highlight potential interactions between amyloid precursor protein (APP) and valosin-containing protein (VCP), and between p53 and 14-3-3 zeta, poten-tially linking proteostasis and stress signaling. Together, these analyses identify a conserved astrocyte-centered network signature that may relate neurodegenerative and cardiovascular processes, and prioritize structurally testable candidates for biomarker and intervention hypothesis testing.
Predicting cellular adaptation proteins dependent on eIF2α regulation under stress conditions: physiological and pathophysiological implications in neuronal function
(Elsevier, 2025) Gürsoy, Attila; Keskin, Özlem; Şenyüz, Simge; Zeylan, Melisa Ece; Zeylan, Melisa Ece; Herrera-Fernández V; Fanlo-Ucar H; Gohl P; Vicente R; Oliva B; Muñoz FJ.; Department of Computer Engineering; Yes; Şenyüz, Simge; College of Engineering
Understanding the intricate mechanisms governing gene expression regulation is crucial for deciphering neuronal responses to cellular stress at both the physiological (i.e., synaptogenesis) and pathophysiological (i.e., neurodegenerative diseases) levels. These rapid adaptive changes depend on the translation of specific proteins with specialized 5′ untranslated regions (5′UTRs), triggered by the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α), while normal cellular translation remains largely inhibited. This study aims to provide a useful tool to identify mRNAs susceptible to regulation by p-eIF2α. We compiled a database of 5′UTRs using Ensembl canonical transcripts from the GRCh38.p14 genome build. Ensembl IDs were used to extract coding sequences and cDNA via the REST API, and 5′UTR regions were identified. We applied translation efficiency-based filters to existing databases of p-eIF2α-dependent translation to obtain reliable training and testing datasets. A multiple logistic regression (MLR) model—using 5′UTR length, GC content, upstream open reading frames (uORFs), and the features of Atf4 as a reference—predicted scores for p-eIF2α-driven translation. Gene Ontology (GO) enrichment analysis identified significant biological processes, molecular functions, and cellular components involved. An interactome analysis using STRING-db highlighted pathways related to synaptoplasticity (physiological stress) and Alzheimer’s disease (pathophysiological stress). In vitro luciferase assays validated SLC30A4 as a novel p-eIF2α-regulated transcript, uncovering the role of eIF2α regulation in zinc homeostasis and neurodegeneration. These findings underscore the importance of translational control mechanisms in memory formation and disease pathogenesis, contributing to the identification of potential therapeutic targets to mitigate pathological outcomes.
