Biology subjects

Grigorean, G.

Publications and source records attributed to Grigorean, G..

4 recordsLinked to original sources

bioRxiv2026

Proteomic comparison of Marburg and Kasokero virus infection in natural host Egyptian rousette bat reveals distinct antiviral pathways

Bats are natural reservoir hosts for numerous zoonotic viruses, yet the molecular mechanisms enabling viral persistence without overt disease remain incompletely understood. The Egyptian rousette bat (Rousettus aegyptiacus, ERB) is the sole known natural reservoir of Marburg virus (MARV) and a key host in the enzootic cycle of the tick-borne Kasokero virus (KASV), providing a unique system to compare host responses to different RNA viruses within the same species. Here, we applied serial cross-sectional serum proteomics integrated with tissue-specific viral kinetics to characterize systemic host responses to experimental MARV and KASV infection in captive-reared bats. Nearly 16 % of detected proteins (67/419) were found exclusively in infected animals, yet canonical acute inflammatory signatures driving pathology in other susceptible hosts were absent (e.g., in humans and non-human primates). Differential abundance and detection analyses identified both shared and virus-dependent responses, with MARV infection eliciting limited and transient perturbations, while KASV induced broader and more sustained engagement of complement, lectin pathway, and hepatometabolic proteins. Network-based analysis uncovered coordinated proteasome modules, including circulating immunoproteasome complexes, consistent with enhanced antigen-processing capacity is a feature of these virus-host dynamics. Together, these findings reveal how ERBs mount structured, virus-dependent systemic responses, offering new insight into mechanisms underlying viral infection in natural reservoir hosts.

systems biology↗

bioRxiv2026

Metabolic Perturbation Exacerbates Sinoatrial Node Dysfunction in Heart Failure

Heart failure (HF) affects approximately 6.2 million people in the United States, with a 5-year mortality exceeding 50%. Bradyarrhythmia, a known complication in HF due to sinoatrial node (SAN) dysfunction (SAND), increases the morbidity and mortality of HF patients. Insights into the mechanistic underpinnings of SAND in HF could therefore uncover vital therapeutic targets to improve clinical outcomes. The SAN cells are endowed with a dense mitochondrial network crucial for sustaining their pacemaking function on a beat-to-beat basis. We have previously demonstrated significant disruptions in the mitochondrial-sarcoplasmic reticulum connectomics, resulting in abnormal mitochondrial Ca2+ handling and impaired mitochondrial function in HF. Here, we hypothesize that the metabolic perturbation is one of the critical mechanisms underlying SAND. To this end, we took advantage of a multi-omics approach combined with ultra-resolution imaging and functional analyses to decipher the metabolic shift that transpires in the HF SAN. Our findings revealed significant metabolic remodeling within the SAN mitochondria in HF, with a diminished reliance on fatty acid {beta}-oxidation, enhanced utilization of ketone bodies, and heightened dependence on carbohydrate catabolism. Notably, metabolomics analyses identified the pronounced increase of glucosylceramides and ceramides as one of the mechanisms leading to mitochondrial dysfunction. We directly test this hypothesis and demonstrate that ceramides induce a dose-dependent metabolic shift from oxidative phosphorylation to glycolysis. Importantly, these alterations lead to a significant impairment in SAN automaticity in a dose-dependent manner. Collectively, the findings support the notion that ceramides are not only markers of metabolic derangement, but also active mediators of mitochondrial and metabolic dysfunction in the SAN. Overall, the study provides evidence that ceramides may be a potential therapeutic target for mitigating SAND in HF.

physiology↗

bioRxiv2025

Molecular interactions of Chd8 in mouse brain highlights a role in chromatin-associated RNA processing

The chromatin remodeler CHD8 is a model risk gene for neurodevelopmental disorders (NDDs). While CHD8 has nucleosome remodeling capacity, evidence suggests it participates in processes beyond chromatin regulation, raising questions about function in the brain and role in NDDs. We defined CHD8 interactions using a comprehensive multimodal omics approach. Immunoprecipitation followed by mass spectrometry (IP-MS) identified a complex interaction network enriched for chromatin remodeling, RNA processing, and cytoskeletal proteins in neonatal mouse forebrain. We implemented CHD8-TurboID in HEK293T cells, validating IP-MS signatures and further identifying a role in mitosis. In addition to DNA, Chd8 complexed with RNA in mouse forebrain, with affinity for genes associated with RNA splicing and nervous system development and overlap between Chd8-bound mRNA and promoters. Finally, Chd8 interaction affinity with RNA splicing factors was reduced in Chd8 haploinsufficient mice. These findings expand understanding of CHD8 function and identify a dosage-sensitive NDD-relevant role in chromatin-associated RNA processing.

molecular biology↗

bioRxiv2025

Context-dependent Interactors Regulate TDP-43 Dysfunction in ALS/FTLD

TDP-43 mislocalization, aggregation, and loss of splicing function are neuropathological hallmarks in over 97% of Amyotrophic Lateral Sclerosis (ALS), 45% of Frontotemporal Lobar Degeneration (FTLD), and 60% of Alzheimers Disease, which has been reclassified as LATE-NC. However, the mechanisms underlying TDP-43 dysfunction remain elusive. Here, we utilize APEX2-driven proximity labeling and mass spectrometry to characterize the context-dependent TDP-43 interactome in conditions of cytoplasmic mislocalization, impaired RNA-binding contributing to aggregation, and oxidative stress. We describe context-dependent interactors, including disrupted interactions with splicing-related proteins and altered biomolecular condensate (BMC) associations. By integrating ALS and FTLD snRNA-seq data, we uncover disease-relevant molecular alterations and validate our dataset through a functional screen that identifies key TDP- 43 regulators. We demonstrate that disrupting nuclear speckle integrity, particularly through the downregulation of the splicing factor SRRM2, promotes TDP-43 mislocalization and loss of function. Additionally, we identify NUFIP2 as an interactor associated with mislocalization that sequesters TDP-43 into cytoplasmic aggregates and co-localizes with TDP-43 pathology in patient tissue. We also highlight HNRNPC as a potent TDP-43 splicing regulator, where precise modulation of TDP-43 or HNRNPC can rescue cryptic exon splicing. These findings provide mechanistic insights and potential therapeutic targets for TDP-43 dysfunction.

molecular biology↗