Biology subjects

Das, S.

Publications and source records attributed to Das, S..

At least 19 recordsLinked to original sources

bioRxiv2026

The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging

The human extracellular-matrix-related FREM3 gene is strongly age-dependent, enriched in age-sensitive excitatory long-range-projecting neurons, and implicated in neurodegenerative diseases. To establish the first translationally relevant causal evidence for the role of FREM3 in brain structure and cognition, we developed an excitatory-neuron-specific Frem3 conditional knockout mouse model (Frem3-cKO) and computed genetically regulated expression of FREM3 (FREM3-GReX) in humans, enabling convergent neurostructural and cognitive characterizations. Frem3-cKO mice showed widespread lower global and regional brain volume in middle age vs young adulthood, consistent with drastic age-dependent volume loss absent in wildtype mice. These effects were strongest in cognitively relevant cortical regions and paralleled by lower cognitive performance. In humans, lower FREM3-GReX was associated with lower total surface area, which further mediated an indirect link to lower cognitive performance across multiple age-sensitive domains. We provide the first translationally relevant cross-species evidence supporting a key role for FREM3/Frem3 in maintaining brain and cognitive health across aging.

neuroscience↗

bioRxiv2026

Dosage-dependent disruption of corticofugal neuron development by Fezf2 loss

Background. Fezf2 (Forebrain Embryonic Zinc Finger 2) is a dosage-sensitive transcription factor required for the specification of corticofugal projection neurons, and rare predicted-deleterious Fezf2 variants are associated with human neurodevelopmental disorders. The cell-type-specific and temporal manner in which Fezf2 dosage shapes cortical development remains incompletely resolved at single-cell resolution. This study aims to quantify the temporal and cell-type-specific transcriptional response to progressive Fezf2 loss by re-analyzing a public single-cell atlas of mouse cortical development. Methods. We re-analyzed 20 single-cell RNA-seq samples spanning embryonic day (E) 10 to postnatal day (P) 4 across wild-type (WT), Fezf2-heterozygous (Het), and Fezf2-knockout (KO) genotypes, together with 3 wild-type single-cell ATAC-seq samples, from Di Bella et al. (2021) (GSE153164). After quality control, consensus doublet removal, and batch integration with two complementary methods (Harmony and scVI), we annotated cell types and quantified genotype effects. Because the source design includes a single library per genotype at most stages, we report effect sizes with bootstrap 95% confidence intervals and calibrate candidate dysregulation against a biological-noise null estimated from the two WT replicates at P1, rather than reporting formal inferential p-values. Results. We recovered 121,889 high-quality cells and 20,982 genes, resolving 17 transcriptionally distinct cell types. The most prominent genotype effect was a dosage-dependent depletion of subcerebral projection neurons (SCPNs) at P1 - the only timepoint at which all three genotypes were sampled: SCPNs comprised 2.21% of WT cells (mean of two replicates) but 0.18% of Het and 0.15% of KO cells, an approximately 13 -15-fold reduction. Using the WT-replicate null (99th percentile |log2 fold-change| = 0.34), we identified 947, 1,119, and 838 genes exceeding this threshold in Maturing, Corticothalamic, and Callosal projection neurons, respectively. Genes downregulated in KO projection neurons were convergently enriched for cytoplasmic translation and ribosome biogenesis (adjusted P {approx} 8.8*10^-30; in Corticothalamic Neurons). Regulon-activity analysis nominated Six4, Atf5, and Myt1 as increased and Hdac7, Rest, and Kdm5a as decreased in KO cells. Conclusions. Progressive Fezf2 loss is associated with a dosage-dependent, cell-type-specific disruption of cortical development, most notably near-elimination of the SCPN compartment by birth and a convergent downregulation of translational/maturation-associated genes across projection neurons. These associations nominate candidate downstream programs for experimental follow-up; they do not by themselves establish a mechanism.

neuroscience↗

bioRxiv2026

Microrobot and Cellbot Locomotion in Confined Hydrogels and Cardiac Tissue Surfaces

Biohybrid cellbots and microrobots are a promising platform for targeted drug delivery, minimally invasive surgery, and tissue engineering. Here, we present a comparative analysis of the locomotion dynamics across synthetic substrates and ex vivo cardiac tissue to help bridge the gap presented by translating locomotion dynamics from idealized environments to biological interfaces. By subjecting the microrobots and cellbots to different substrates (specifically, cell culture dish, hydrogel, and ex vivo tissue) and applying rotating magnetic fields at varying frequencies, we characterized how surface boundary interactions and driving frequency dictate translation speed. We reveal that particles moving on tissue exhibit restricted movement based on trajectory and tissue fiber orientation. Finally, we discuss that while cellular integration introduces significant adhesive drag that reduces translation speeds, it simultaneously offers a unique clinical advantage. This study highlights the potential of balancing magnetic driving parameters against biological environments to optimize for various treatment timelines and efficiency across diverse biomedical applications.

bioengineering↗

bioRxiv2026

PlasmoRhythm: A comprehensive database for malaria-associated rhythmic transcripts, proteins, and metabolites

Abstract: Motivation: The malaria transmission cycle is temporally organized across three interacting biological systems: the parasite, vertebrate host, and mosquito vector. Rhythms in parasite development, host physiology, and vector behavior govern infection dynamics, transmission, and the efficacy of stage-specific antimalarial interventions. However, the molecular architecture connecting these rhythms remains difficult to interrogate because time-resolved omics datasets are distributed across species, experimental paradigms, and analytical frameworks, with no unified resource for comparative analysis. Results: We developed PlasmoRhythm, a curated database integrating 67 transcriptomic, proteomic, and metabolomic datasets from 15 studies, encompassing 1,126 sampling events across Plasmodium species, mammalian hosts, and Anopheles vectors. Harmonized metadata and rhythmicity outputs from JTK_CYCLE, ARSER, Lomb-Scargle, and the meta2d function support interactive cross-study interrogation of molecular profiles. Dedicated modules enable the exploration of rhythmic virulence factors and antimalarial drug interactors, providing a unified framework for hypothesis generation across the malaria transmission cycle. Availability: PlasmoRhythm is freely accessible at https://project.iith.ac.in/cgntlab/PlasmoRhythm/.

bioinformatics↗

bioRxiv2026

A complex balance: PLETHORA - JANUS ratiometry explains the PLETHORA dosage regeneration paradox

Molecular gradients are classically thought to encode positional information through concentration thresholds, but how transcription factor dosage is translated into regenerative competence remains unclear. In Arabidopsis roots, PLETHORA (PLT) transcription factors form a gradient that defines a regeneration competence zone and, following injury, rapidly re-establishes their transcriptional domain through an auto-activation. Yet, increasing PLT levels has a paradoxical effect: moderate increases expand the competence zone, whereas further increases impair regeneration. Here, combining mathematical modelling with experiments, we uncover the molecular basis of this non-monotonic response. Our model reveals that PLT activity depends not simply on its abundance, but on the balance between PLT protein complexes and unbound PLT. Following injury, PLT auto-activation rapidly restores the transcriptional domain, whereas increasing PLT dosage progressively shifts the equilibrium towards unbound PLT, reducing the availability of active PLT complexes. We identify and experimentally validate a strategy to extend regeneration competence by maintaining an appropriate ratio of PLT complexes to unbound PLT. Our findings reveal a ratiometric mechanism for decoding transcription factor dosage, in which excess regulator can attenuate rather than enhance activity. Such molecular balancing provides a mechanism by which a single transcription factor gradient can generate distinct, context-dependent outcomes during development and regeneration.

developmental biology↗

bioRxiv2026

Separation, isolation, and membrane lipid profiling of selectively vulnerable and resilient neurons

Certain neurons are more susceptible to pathogenic stressors and degenerate, while others remain resilient in neurodegenerative diseases. However, the mechanisms underlying this cell-to-cell heterogeneity in neuronal vulnerability remain unclear, primarily due to challenges in isolating vulnerable and resilient neurons to characterize their properties. In this study, we report the development of a novel cell-labeling method utilizing two cell-impermeable dyes to identify vulnerable and resilient neurons in culture, which are subsequently separated and isolated via fluorescence-activated cell sorting (FACS). As a proof-of-concept of a mechanistic study, we conducted lipidomic analysis to determine whether the lipid composition of membranes differs between vulnerable and resilient neurons to oxidative stress. This simple but unique method sets the groundwork for investigating the molecular underpinnings of selective neuronal vulnerability, which could inform new diagnostic strategies and therapeutic targets for neurodegenerative diseases.

neuroscience↗

bioRxiv2026

Conserved molecular compatibility for MIZ1 function in cytokinin signaling in land plants

Plant roots adjust their growth direction toward water through hydrotropism, a process that in Arabidopsis thaliana requires the endoplasmic reticulum (ER)-associated protein MIZU-KUSSEI1 (MIZ1). Nonetheless, MIZ1 orthologues occur throughout land plants, including lineages lacking true roots, raising questions about the ancestral function of this protein family. Here, we investigated the evolutionary conservation and functional diversification of MIZ1-like proteins across land plants. MIZ1 orthologues from evolutionarily distant land plants failed to restore hydrotropism or cytokinin sensitivity in the Arabidopsis miz1 mutant, despite conserved protein structure and ER localization. In the liverwort Marchantia polymorpha, loss of MpMIZ1a led to altered cytokinin sensitivity and cytokinin-mediated development in both the sporophyte and gametophyte. These phenotypes and gene expression analyses imply a conserved role of MIZ1 in cytokinin-related processes. Despite this functional similarity, protein-protein docking and bimolecular fluorescence complementation revealed species-specific interactions between MIZ1 proteins and their cognate cytokinin histidine kinase receptors in Arabidopsis and Marchantia. Together, our findings indicate that MIZ1 proteins represent ancient land plant regulators of cytokinin-dependent development whose molecular compatibility and developmental outputs have diverged during evolution. We propose that the role of MIZ1 in root hydrotropism represents a derived recruitment of this ancestral module into root-specific environmental response pathways.

plant biology↗

bioRxiv2026

The scaffold nucleoporin Nup188 undergoes liquid-liquid phase separation

Components of nuclear pore complexes are broadly classified into two categories: intrinsically disordered FG-repeat nucleoporins such as Nup98, which can undergo liquid-liquid phase separation, and scaffold nucleoporins, which form the NPC's structural framework. The basis for crosstalk of these nucleoporins within NPC and beyond is poorly understood. Here we show that human Nup188, a helical inner-ring scaffold protein, forms condensates both in purified form as well as at endogenous level. This condensate exhibits fusion, dissolved in 1,6-hexanediol and recovered after photobleaching, with dynamics and material properties comparable to those of hNup98 condensates. Moreover, these condensates are not colocalized to annulate lamellae. Our analysis also revealed that hNup188CTD is sufficient to form condensates and MD simulations revealed the key roles of IDR1-3 for condensation. Notably, hNup93 expression along with hNup188 suppressed the condensate formation. Together, these findings indicate that a structured scaffold nucleoporin can adopt a condensate-forming state via its CTD and Nup93 binding can suppress this phenomenon.

biochemistry↗

bioRxiv2026

SMYD3 protein degraders in HPV-negative head and neck squamous cell carcinoma.

Despite the advent of immunotherapy in the treatment of human-papilloma-virus (HPV)-negative head and neck squamous cell carcinoma, the overall prognosis still remains dismal. Novel therapeutic approaches are thus urgently needed. We recently reported that SET and MYND containing 3 (SMYD3), a protein methyltransferase that is known to activate the transcription of its target genes through H3K4me3, is overexpressed in ~60% of HPV-negative HNSCC tumors, it drives proliferation and invasion, and induces resistance to immunotherapy in HPV-negative HNSCC. These phenotypes are mediated partially through transcriptional regulation of cell cycle, EMT and immune-related target genes by SMYD3. Despite its enzymatic inhibitory potency in HPV-negative HNSC cell lines, the commercially available SMYD3 inhibitors EPZ031686 and BAY-6035 demonstrated no in vitro phenotypic efficacy in these cell lines, supporting that SMYD3 exerts its oncogenic functions predominantly through catalytically-independent mechanisms. Thus, to effectively target SMYD3, we designed a series of SMYD3 proteolysis targeting chimeras (PROTACs). Treatment of HPV-negative HNSCC cell lines with SMYD3 PROTACs at nanomolar concentrations degraded SMYD3 effectively and induced a drastic decrease in the proliferative and invasive potential of HPV-negative HNSCC cells. One of the designed compounds, IAP-08, showed a promising DC50 at ~177nM with Dmax of ~90%, and effectively induced the formation of ternary complexes with SMYD3 and the XIAP E3 ligase. Furthermore, IAP-08 showed a favorable pharmacokinetic profile in vivo, underscoring the feasibility for further clinical development of this compound. Mass spectrometry analysis of IAP-08 supported its high specificity towards SMYD3. SMYD3 depletion by IAP-08 in HNSCC cells revealed transcriptional regulation of cell cycle, EMT- and type I IFN response genes, in contrast to SMYD3 inhibition which had only a weak transcriptional effect. In summary, we show that inhibition of the enzymatic activity of SMYD3 is not sufficient to repress its oncogenic activity and provide evidence that depletion through PROTACs effectively targets the oncogenic functions of SMYD3 in HPV-negative HNSCC.

cancer biology↗

bioRxiv2026

A tRNA-derived small RNA orchestrates cardioprotection through distinct cell-type-specific mechanisms

Pathological cardiac fibrosis and hypertrophy, key contributors to adverse remodeling that drives heart failure (HF), are not adequately targeted by current therapies. We identified tRNA-Asp-GTC-3'tDR, an ischemia-induced tRNA-derived small RNA (tDR), as an endogenous regulator of both remodeling processes across cardiac fibroblasts and cardiomyocytes. In murine models of myocardial ischemia- and pressure overload-induced HF, cardiac delivery of tRNA-Asp-GTC-3'tDR reduced fibrosis and hypertrophy, preserved cardiac function, and improved survival, with limited three doses conferring durable protection after ischemia, whereas silencing it worsened both. Strikingly, tRNA-Asp-GTC-3'tDR acts through distinct mechanisms in different cell types: in fibroblasts, it assembles stress granules that sequester ribosome-loaded profibrotic transcripts, whereas in cardiomyocytes it engages pseudouridine synthase PUS7 to activate RNA autophagy. Its regulation and functions were confirmed in human cardiac cells and tissues. These findings demonstrate that a single tDR coordinates cell-type-specific protective programs in the heart, suggesting a new therapeutic axis to mitigate HF progression.

cell biology↗

bioRxiv2026

Targeted and bilateral blood flow monitoring in middle cerebral artery using diffuse correlation spectroscopy

Objective: To develop and validate a dual-probe Diffuse Correlation Spectroscopy (DCS) system for non-invasive and simultaneous, monitoring of cerebral blood flow (CBF) in the bilateral Middle Cerebral Artery (MCA) territories, and expanding the utility of conventional DCS limited to cortical-volume-based CBF measurements to vessel-specific cerebral perfusion monitoring. Methods: A dual-probe DCS system was designed for non-invasive monitoring of MCA-specific perfusion. Probe placement and protocol optimization study has been performed using anatomical landmarks, motor and speech activation tasks in healthy volunteers. System stability and repeatability were further evaluated in a pilot cohort of 30 healthy (age, 25{+/-}7 years) participants using optimized probe position and protocol. A bilateral MCA ischemic Lacunar Infract stroke case report also validated the feasibility of the system in clinical settings. Results: Measurements demonstrated superior sensitivity towards MCA-territory perfusion at targeted probe locations compared to off-MCA positions. In pilot cohort, significant increase of 30.34 {+/-} 21.56% and 36.48 {+/-} 21.22% in rCBF corresponding to hand squeeze and speech task respectively showed reproducible physiological responsiveness of the system (p<0.001). Measurement done on a patient with bilateral MCA ischemic Lacunar Infract stroke showed a significant change of 30% during speech for both the MCAs but no significant change is observed for hand squeeze tasks. Conclusion: The custom built dual-probe DCS system enables non-invasive, operator-independent, targeted and continuous monitoring of rCBF within bilateral MCA territories. Significance: This approach enables the potential use of DCS system for bilateral and vessel-specific monitoring of cerebral perfusion in the MCA territories.

bioengineering↗

bioRxiv2026

Collateral Immune Cell Signaling Compromises the Efficacy of T-cell Engaging Therapies for Cardiac Fibrosis

Cardiac fibrosis is causally linked to heart failure progression and survival. Currently, there are no approved treatments that directly target cardiac fibrosis. Recent studies have identified a subset of activated cardiac fibroblasts distinct from myofibroblasts that are marked by fibroblast activation protein (FAP) expression, emerge in the injured and diseased heart through inflammatory signaling, and contribute to fibrosis. Using a genetic mouse model, we demonstrate the potential benefits of FAP+ fibroblast depletion following myocardial infarction. Unexpectedly, while FAP targeted bispecific T-cell engaging antibodies (BiTE(R) molecules) effectively eliminate FAP+ fibroblasts from the heart, they surprisingly lead to accelerated deterioration of cardiac function, enhanced remodeling, and increased scar size. FAP BiTE(R) molecules elicit a robust cytokine response within the heart with prominent activation of interferon gamma (IFNg) and CD40 ligand pathways. Target cell killing was independent of IFNg; and CD40L signaling and blockade of these pathways was sufficient to unmask the protective therapeutic effects of FAP+ fibroblast depletion. Mechanistically, we reveal that IFNg; signaling to fibroblasts drives the differentiation of an independent lineage of activated fibroblasts not typically found in the infarcted heart, which are responsible for the harmful effects of FAP BiTE(R) molecules. Collectively, these findings highlight a previously unrecognized cardiac liability of BiTE(R) molecules and inform the design of the next generation of therapeutics.

immunology↗

bioRxiv2026

Comparative analysis of immunomodulatory effects of Artemisinin and Parthenolide on activation of immune cells and their roles in Salmonella Typhimurium infection

Plant-derived immunomodulators are of immense therapeutic interest, of which sesquiterpene lactones (SLs) are a promising source. Artemisinin and Parthenolide are two structurally related SLs that are known to inhibit NF-{kappa}B. However, whether this mechanism produces comparable immunomodulatory outcomes has not been directly examined. In this study, we compared the effects of Artemisinin and Parthenolide across different in vitro and in vivo inflammatory contexts: T-cell activation, macrophage activation, and Salmonella Typhimurium infection. Parthenolide inhibited mouse T-cell activation more effectively than Artemisinin in terms of cell cycling, IL-2 production, and induction of activation markers, CD69 and CD44. In addition, Parthenolide suppressed production of LPS-induced nitrite and pro-inflammatory cytokines in primary thioglycolate (TG)-elicited macrophages as well as RAW 264.7 cells. It also reduced ROS production across all tested conditions. In contrast, Artemisinin exhibited comparatively modest effects, although it increased IL-6 in LPS-activated RAW 264.7 cells. Neither compound reduced bacterial burden in an in vitro model of S. Typhimurium infection; however, Parthenolide, but not Artemisinin, lowered TNF- amounts. Together, these findings demonstrate that Parthenolide is a broader and more consistent immunomodulator than Artemisinin. These observations led us to investigate the effects of Parthenolide in an in vivo model of mice orally fed with S. Typhimurium. Parthenolide-treated mice showed higher survival accompanied with lower sera amounts of IL-6 and TNF-, indicating that its protective effects operate by limiting host immunopathology. The implications of these observations on the use of compounds that lower host inflammatory responses during infections are discussed.

immunology↗

bioRxiv2026

Spatially resolved gene expression and tumour-microenvironment interactions across malignant transformation in IDH-mutant glioma

Isocitrate dehydrogenase (IDH)-mutant gliomas represent most lower-grade diffuse gliomas in young adults. Although IDH-mutant gliomas initially behave indolently relative to IDH-wildtype counterparts, they undergo inevitable malignant transformation. The mechanisms driving this progression remain poorly defined. We analyzed a unique longitudinal cohort of two patients with IDH-mutant diffuse gliomas, each with matched WHO grade 2, 3, and 4 tumours. Spatial transcriptomics (NanoString GeoMx and 10X Visium), combined with differential expression, spatially variable gene analysis, and gene ontology enrichment, were used to define transcriptional programs underlying progression. Unexpectedly, across both patients, higher-grade tumours demonstrated reduced proliferation at the infiltrative margin as measured by Ki67. Spatial transcriptomic analysis identified an enrichment of invasion-associated genes associated with increasing tumour grade. In an independent bulk RNA-seq cohort, expression of this spatially derived program did not outperform grade-only PFS or OS analysis. These observations underscore the need to develop new metrics that account for spatial evolution that occurs across progression, but escapes detection in bulk analyses and provide the rationale for prioritizing migration-, cytoskeletal- and stress-associated programs for further investigation.

cancer biology↗

bioRxiv2026

Oncolytic virus-antibody combinations enhance immune-mediated killing of osteosarcoma

A major barrier to effective immunotherapy in osteosarcoma (OS) is the highly immunosuppressive tumour microenvironment (TME), which limits immune recognition and elimination of tumour cells. We evaluated a panel of oncolytic herpes simplex viruses (oHSVs) for their direct oncolytic activity, immune-modulatory properties and capacity to counteract OS-associated immunosuppression using immunologically relevant in vitro models. We demonstrate that established OS cell lines, primary cell cultures and dissociated OS cells from freshly resected tumour samples are susceptible to direct oncolysis by three oHSVs; HSV1716, HSV1716-GMCSF, and HSV47{Delta}, although susceptibility levels varied. Treatment of peripheral blood mononuclear cells from healthy donors and OS patients with oHSVs enhanced natural killer (NK) cell activation and promoted immune-mediated killing of OS cell lines and primary OS cell cultures. Among the three viruses, HSV1716-GMCSF exhibited the strongest immune-stimulatory effects and was uniquely capable of reducing the abundance of CD163+CD206+ immunosuppressive TAMs; use of this oHSV was therefore prioritised. We developed a multicellular spheroid model of OS, incorporating OS cells, mesenchymal stem cells and TAMs, which exhibits resistance to immune-mediated killing, better reflecting the immunosuppressive TME in patients. In this model, pairing HSV1716-GMCSF treatment with either anti-GD2 or anti-EGFR monoclonal antibodies (mAbs), selected according to OS tumour antigen expression, significantly increased immune-mediated tumour cell killing. These findings suggest that personalised combination strategies pairing oHSVs with appropriate mAbs provide a promising therapeutic approach for OS by integrating direct oncolysis, remodelling of the immunosuppressive TME and enhanced immune-mediated tumour destruction.

cancer biology↗

bioRxiv2026

Predicting Speech in Noise Perception using Measures of Neural Entrainment

Speech perception ability in a cocktail party environment is highly variable, even for people with clinically healthy hearing. The mechanisms of these differences are poorly understood. A possible reason for these differences could be due to the neural mechanisms of auditory attention. This investigation aims to quantify how well a person is able to neurally entrain to a continuous narrative using a temporal response function (TRF), then evaluate if that TRF measure is correlated with an individual's performance on a selective attention and narrative comprehension task. This was accomplished using a cohort of twenty-five young and healthy listeners who completed speech-in-noise (SIN) perception tasks while their neural activity was recorded with EEG. This EEG data and regressors (speech envelope and gammatone spectrogram) of an auditory stimulus was used to train TRF models. TRF cross validation correlation coefficients were then used in multiple regression models to predict a participant's SIN performance. Task performance had a significant positive relationship with the neural entrainment to an attended stimulus and a negative relationship with the neural entrainment to an unattended stimulus. This was observed with both the selective attention and narrative comprehension measures. The difference of the attended and unattended correlation coefficients were also significantly related to increased task performance. These measures could be a potential biomarker to predict an individual's speech perception in a noisy environment.

neuroscience↗

bioRxiv2026

Type II topoisomerase substrate geometry revealed through combined experiment and computation.

Type II topoisomerases (topo IIs) are essential enzymes that regulate DNA topology through a strand-passage mechanism in which a duplex DNA (transfer-segment) is passed through a transiently cleaved second duplex DNA (gate-segment). Biochemical and structural approaches have revealed critical details of the binding and cleavage of the gate-segment DNA. However, capture of the transfer-segment DNA has proven more difficult to resolve due to the transient nature of the interaction. Nonetheless, selection of the transfer segment with a specific conformation or orientation relative to the gate segment is predicted to govern aspects of topo II activity, including chiral discrimination and the ability to reduce topological complexity below equilibrium. To determine the conformation and orientation of the transfer-segment relative to the gate segment, we combined experimental single-molecule measurements of topo II unlinking a single DNA crossing with Brownian dynamics simulations of the DNA crossing. By correlating the unlinking rate with the geometric features of the DNA crossing, we obtain the complete three-dimensional preferred crossing geometry for strand passage. Strikingly, the preferred crossing geometries for Escherichia coli topoisomerase IV and Methanosarcina mazei topoisomerase VI are distinct and provide structural models of the DNA synapse selected for strand passage along with a mechanistic basis for their differing activities and biological functions. The approach we develop is generalizable, providing unique insights into the kinetic selection of DNA synapse structure.

biophysics↗

bioRxiv2026

Aberrant accumulation of α-synuclein might be linked with the progressive motor deficits in a mouse model of Angelman syndrome

Dysfunction of maternal UBE3A leads to Angelman syndrome (AS), which is characterized by significant intellectual and motor debilities. However, the molecular underpinnings of the behavioral deficits associated with UBE3A dysfunction remain obscure. In this study, we utilized a model mouse of AS and report, for the first time, that the aberrant accumulation of -synuclein may be linked to the development of AS. Firstly, we demonstrated a progressive deterioration of various motor functions in AS mice beginning from the early adolescent phase. Subsequently, we observed an age-dependent increase in the accumulation of both soluble and insoluble -synuclein, including its pathological variant (pSer129), in the striatum and substantia nigra dopaminergic neurons of AS mice. We also found that Ube3a interacts with -synuclein and promotes its proteasome-mediated degradation, as evidenced by decreased levels of K48-linked polyubiquitinated -synuclein in the brain samples of AS mice in comparison to wild-type animals. Finally, using an RT2 Profiler PCR Array that analysed 84 genes specifically related to dopamine and serotonin pathways, we identified altered transcript level of various genes in the striatal tissues of AS mice that are commonly associated with nigrostriatal dysfunctions in Parkinson's disease. These findings highlight -synuclein as a novel target of Ube3a and suggest that -synuclein pathology may contribute to the progressive motor and other behavioral abnormalities witnessed in AS mice.

neuroscience↗