Biology subjects

Vilkaite, G.

Publications and source records attributed to Vilkaite, G..

3 recordsLinked to original sources

bioRxiv2026

Beyond organ age gaps: comparing plasma proteomic metrics of organ biology in relation to brain structure and neurodegenerative disease.

Biological aging is heterogeneous across organ systems, and brain health may be influenced by biological processes extending beyond the central nervous system (CNS). This can be investigated using biological age measures that are increasingly used to estimate how biological systems deviate from chronological aging. However, organ level plasma proteomic metrics may capture different forms of biological variation depending on how they are defined. Here, we compared three complementary organ level proteomic metrics across 15 organ systems (and two global systems) in relation to age, organ-relevant physiological phenotypes, brain morphometry, and incident neurodegenerative disease, using plasma proteomics from 52,667 UK Biobank participants and brain MRI data from 5,078 of those individuals. We derived i) supervised age gap metrics using XGBoost models trained to predict chronological age, ii) unsupervised PC1 metrics capturing dominant organ-associated proteomic variation, and iii) phenotype guided PLS metrics linking plasma proteins to organ-relevant physiological traits. The three metric classes were related but not interchangeable. Global all-protein and all-organ-protein models showed strong age-related proteomic structure. However, organ-specific PC analyses showed that age was often but not always the dominant source of variation in protein signal across organs. Age gap metrics showed the most consistent associations with subsequent ICD-10-based neurodegenerative and vascular diagnoses, whereas all three metric classes showed distinct associations with brain structure and organ-relevant physiological phenotypes. Brain structure analyses revealed heterogeneous organ-brain association patterns across organs, suggesting that proteomic variation relates to brain structure in both a systemic and an organ-specific manner. Several systemic and organ-specific signals partially mediated the associations between disease specific genetic risk and incident diagnoses of Alzheimer's disease and stroke, albeit with small effect sizes (1-8%). Similarly, organ metrics provided modest incremental predictive improvement over baseline demographic models, with the largest increase in ROC-AUC observed for Alzheimer's disease when all organ age gap metrics were added jointly (delta ROC-AUC = 0.037). These results link brain related outcomes to proteomic variation across both CNS and non-CNS systems. Our work suggests that proteomic organ metrics capture complementary dimensions of biological variation rather than a single construct of organ aging. Although these measures may provide informative biological and potentially predictive signals, their incremental predictive value in the present analyses was modest.

neuroscience↗

bioRxiv2026

A coordinated and reproducible multicellular response to AD pathology

While single-cell measurements of the Alzheimer's disease (AD) brain allow investigation of vulnerable cells in unprecedented depth, reported findings are heterogeneous, mostly descriptive and often ignore interdependence of cellular responses. Operationalization of these findings requires a multi-cellular model of AD that is robust and reproducible. Here, we utilize a coordinated multicellular community approach across 2.3 million nuclei from 427 ROSMAP donors to identify robust multicellular axes associated with AD pathology and sex. The AD signature comprised profound alteration to RORB-GABRG excitatory neurons and disrupted oligodendrocyte precursor cell signaling. A separate set of AD-related cell-type specific molecular processes with strong sexual dimorphism also emerged. Importantly, these signatures developed and ROSMAP predicted neuropathology and sex, respectively, in a completely independent dataset (SEA-AD). These findings altogether summarize a highly consistent multi-cellular response to AD pathology in the human brain, creating a baseline cellular model to which perturbation and treatment experiments can be compared.

neuroscience↗

bioRxiv2025

Familial ALS/FTD-associated RNA-Binding deficient TDP-43 mutants cause neuronal and synaptic dysregulation in vitro

TDP-43 is an RNA-binding protein constituting the pathological inclusions observed in [~]95% of ALS and [~]50% of FTD patients. In ALS and FTD, TDP-43 mislocalises to the cytoplasm and forms insoluble, hyperphosphorylated and ubiquitinated aggregates that enhance cytotoxicity and contribute to neurodegeneration. Despite its primary role as an RNA/DNA-binding protein, how RNA-binding deficiencies contribute to disease onset and progression are little understood. Among many identified familial mutations in TDP-43 causing ALS/FTD, only two mutations cause an RNA-binding deficiency, K181E and K263E. In this study, we used CRISPR/Cas9 to knock-in the two disease-linked RNA-binding deficient mutations in SH-SY5Y cells, generating both homozygous and heterozygous versions of the mutant TDP-43 to investigate TDP-43-mediated neuronal disruption. Significant changes were identified in the transcriptomic profiles of these cells, in particular, between K181E homozygous and heterozygous cells, with the most affected genes involved in neuronal differentiation and synaptic pathways. This result was validated in cell studies where the neuronal differentiation efficiency and neurite morphology were compromised in TDP-43 cells compared to unmodified control. Interestingly, divergent neuronal regulation was observed in K181E-TDP-43 homozygous and heterozygous cells, suggesting a more complex signalling network associated with TDP-43 genotypes and expression level which warrants further study. Overall, our data using cell models expressing the ALS/FTD disease-causing RNA-binding deficient TDP-43 mutations at endogenous levels show a robust impact on transcriptomic profiles at the whole gene and transcript isoform level that compromise neuronal differentiation and processing, providing further insights on TDP-43-mediated neurodegeneration.

neuroscience↗