Biology subjects

Senthil, S.

Publications and source records attributed to Senthil, S..

4 recordsLinked to original sources

bioRxiv2026

Multimodal Fusion of Circular Functional Data on High-resolution Neuroretinal Phenotypes

Progressive optic neuropathies, particularly glaucoma, represent a significant global health challenge, and the need for precise understanding of heterogeneous neurodegenerative phenotypes cannot be overstated. Here, we brought together two complementary sources of unstructured yet clinically relevant information about neuroretinal rim (NRR) thinning, a common clinical marker of such decay. These are based on a new dataset of fundus digital images and a corresponding dataset of optical coherence tomography, both collected from a large clinical cohort of healthy eyes. First, we represented them using a common data structure that imposed a high-resolution scale of 180 equally spaced and registered measurements on a 360{degrees} circular axis. We modeled the NRR measurements of each eye as circular curves and aligned these multimodal curves to obtain a fused NRR curve for each eye. Unsupervised clustering of these fused curves identified four clusters of eyes with structural heterogeneity, which were also found to have distinctive clinical covariates. Computation of functional derivatives revealed troughs in the curves of each cluster. Using circular statistics, we estimated the directional distributions of these troughs as potentially clinically relevant regions of NRR degeneration. A comparative study using landmark registration based on functional canonical correlation analysis demonstrated that our curve-alignment-based multimodal fusion is superior. Moreover, it improves the robustness of baseline NRR data obtained from fundus imaging.

bioinformatics↗

bioRxiv2025

RNA-Binding Protein NF90 Mediates Polycomb-Independent Transactivation by EZH2 to Promote Cancer Growth

Increasing evidence suggests critical roles of the polycomb-independent transactivation function of EZH2 in promoting some cancers, such as prostate cancer (PCa), yet the underlying mechanism remains poorly understood. Here, we identify the RNA-binding protein NF90 as a key mediator of this activity. NF90 interacts with EZH2, but not with other core components of the polycomb repressive complex 2 (PRC2), through its RNA-binding modules. Conversely, EZH2 engages NF90 via its intrinsically disordered RNA-binding domain in an RNA-dependent manner. NF90 and EZH2 mutually recruit each other to the AR promoter, where they cooperatively activate AR transcription and enhance downstream AR signaling. This NF90-EZH2 complex is essential for PCa cell growth: depletion of either factor abolishes proliferation, an effect rescued by AR re-expression. Similar to EZH2, NF90 promotes cell-cycle gene expression, is upregulated in advanced PCa, and is associated with poor clinical outcomes. Collectively, our findings uncover RNA-mediated protein interactions as a central mechanism underlying PRC2-independent transcriptional activation by EZH2 and establish NF90 as a major EZH2 coactivator, a master regulator of the cell cycle, and a promising therapeutic target in advanced PCa.

cell biology↗

bioRxiv2025

A Novel Mouse Model of Parkinson's Disease for Investigating Progressive Pathology and Neuroprotection

Developing animal models that successfully recapitulate the features of progressive Parkinsons disease (PD) is crucial for understanding disease progression mechanisms and creating effective therapeutic interventions. In this study, we created a mouse model of PD by overexpressing -synuclein through a combined injection of AAV6--synuclein and preformed fibrils (PFFs) into the medial and lateral substantia nigra (SN). We also demonstrated that chronic administration of the c-Abl inhibitor PD180970 provides neuroprotection in this model. Mice injected with the AAV6--synuclein and PFF combination showed a progressive loss of dopaminergic (DA) neurons in the SN and their projections in the striatum over 24 weeks. This neuronal loss coincided with a time-dependent accumulation of phosphorylated -synuclein (p-syn) in the SN. The p-syn aggregates spread to synaptically connected DARPP-32-positive neurons in the striatum and further extended to the cortex. We also observed a contralateral spread of p-syn aggregates. Additionally, -synuclein overexpression led to a significant increase in activated microglia and astrocytes at all timepoints, with the strongest activation occurring early and gradually diminishing over time. Daily administration of PD180970 significantly reduced the loss of DA neurons caused by -synuclein injection and decreased the accumulation of p-syn in the SN. PD180970 treatment also reduced the neuroinflammation significantly. Overall, the combined injection of AAV6--synuclein and preformed fibrils into the mouse brain establishes a robust PD model, enabling detailed mechanistic studies of the disease. We further demonstrate the models utility for chronic neuroprotection studies using the potential drug PD180970, highlighting its broad applicability. Significance StatementThis study establishes a robust mouse model of Parkinsons disease (PD) by combining AAV6-mediated -synuclein overexpression and preformed fibrils (PFFs) to replicate key features of PD, such as progressive dopaminergic neuron loss, phosphorylated -synuclein accumulation, and neuroinflammation. The model captures the spread of pathological aggregates to synaptically connected brain regions, closely mimicking the human disease. By testing the c-Abl inhibitor PD180970, we demonstrate its neuroprotective effects, including reduced neuronal loss, decreased -synuclein accumulation, and neuroinflammation highlighting its therapeutic potential. This model offers a valuable platform for investigating PD mechanisms and evaluating novel interventions, bridging the gap between preclinical and clinical applications.

neuroscience↗

bioRxiv2025

Small molecule promoters of endogenous lipid droplet accumulation drive lysophagy

Lipid droplets (LDs) play a central role in regulating metabolism in stress-induced conditions, including one triggered by nutrient deprivation. Unravelling the protein networks involved in the biogenesis of LDs and their causative and functional roles in health and disease continue to evolve. To this cause, genetic manipulation of the lipid metabolic network or supplementation of high fat diet/ oleic acid (OA) are the traditional routes for voluntarily triggering LDs formation in cells and animals. We developed a screening platform for the identification of new LDs inducers, and our primary screening of various fatty acids identified linoleic acid (LOA, DUFA) as a better tool than OA (MUFA) in promoting LDs formation. The screening and validation discovered new small molecule-based tools for promoting a rapid organization of endogenous lipids into droplets in multiple cell types. Notably, our mass spectral lipidomics analysis presented the overproduction of phosphatidylcholines and small triglycerides, a hallmark of LDs. Mechanistic investigations of our lead molecules highlighted lipid peroxidation and ATP depletion through mitochondrial impairment in cells, which could serve as chemical cues for driving the fusion of cellular lipids into LDs. Finally, we uncovered the abrupt levels of LDs formation induced by our molecules promoted lysophagy in cancer cells to prevent their proliferation. Collectively, our work introduces new small molecules as powerful tools for reliably promoting LDs accumulation for studying their roles in biology, and we demonstrate the over accumulation of LDs prevent cancer cell proliferation, movement, and colonization.

cancer biology↗