Biology subjects

Ishikawa, T.

Publications and source records attributed to Ishikawa, T..

At least 19 recordsLinked to original sources

bioRxiv2026

A reversible GNAS-PKA-RUNX2 checkpoint governs skeletal stem cell fate in fibrous dysplasia

Fibrous dysplasia (FD) arises from activating GNAS mutations that increase cAMP signaling in skeletal stem/progenitor cells (SSPCs), but the underlying mechanisms and whether the resulting fate imbalance can be reversed remain unclear. Using controlled GNAS induction with transcriptomic, pharmacologic, and cell-fate analyses, we identify a PKA-dependent checkpoint governing SSPC lineage commitment. GNASR201C redirects SSPCs toward osteoclastogenesis while suppressing osteoblast maturation; genetic or pharmacologic PKA inhibition reverses both effects, revealing this fate decision is dynamically reversible. Mechanistically, PKA phosphorylates RUNX2, the master regulator of osteogenesis, enforcing its cytoplasmic retention and blocking osteogenic transcription; a non-phosphorylatable RUNX2 mutant restores nuclear localization and osteoblast differentiation, defining RUNX2 phosphorylation as a disease-initiating molecular switch. Critically, PKA inhibition in vivo reduces fibrosis and osteoclast burden in established bone lesions, demonstrating reversibility even in advanced FD. These findings define a druggable GNAS-PKA-RUNX2 checkpoint and identify PKA inhibition as a strategy to reverse existing disease in FD.

cell biology↗

bioRxiv2026

Novel protein networks in motile cilia from human epithelial cells revealed by cryo-ET and proteomics analysis of cilia from PCD patients

In our past study on human cilia from primary ciliary dyskinesia (PCD) patients using cryo-electron tomography and mass spectrometry, defects in the DNAH5 gene were proven to cause the loss of the entire outer dynein arm along with other proteins. This phenomenon was not observed in the unicellular green alga Chlamydomonas. In this study, we examined the loss of ciliary components caused by defects in various genes, based on proteomic and structural analyses of motile cilia from multiple PCD patients. The absence of single outer arm dynein genes causes a loss or significant decrease in other inner and outer arm dyneins. Interestingly, some patients with outer dynein defects show decreased intraflagellar transport (IFT) proteins, suggesting an influence of cargo components or assembly on transport. These phenomena were not observed in Chlamydomonas, suggesting a more complex mechanism of ciliogenesis in humans despite the high similarity in the final 3D architecture of the 9+2 axoneme. Defects in certain central pair proteins unexpectedly reduced components on the doublets as well. Our results demonstrate protein-protein interactions during stages of human motile ciliogenesis that are more complex than those in unicellular organisms.

cell biology↗

bioRxiv2026

Physics-aware measurement-supervised deep learning enables point spread function inversion in soft X-ray tomography

Soft X-ray tomography (SXT) is an emerging modality for whole-cell 3D imaging in near-native states. However, the effective spatial resolution is limited by optical artifacts characterized by the point spread function (PSF). Standard reconstruction methods force a compromise between structural sharpness and noise, failing to fully resolve these depth-dependent artifacts. By embedding experimentally measured, depth-variant PSFs into a differentiable forward model, we demonstrate a physics-aware computational optimization that bypasses these limitations to recover high-frequency cellular ultrastructure. The structural fidelity was validated using split-tilt Fourier ring correlation (FRC), alongside an experimental bead phantom tomogram, providing supporting evidence that the recovered high-frequency features reflect genuine specimen structure rather than fabricated artifacts. Our method effectively increases FRC spatial resolution and recovers cellular ultrastructure. Furthermore, under sparse-angular subsampling, the framework maintained spatial resolution using half the projection angles, a computational proxy pointing toward the potential for reduced radiation exposure in future acquisitions. This hardware-free, computational approach offers a route toward mitigating the optical and dosimetric constraints that currently limit nanoscale soft X-ray tomography.

Cell Biology↗

bioRxiv2026

BasalCell: A project scaffold generator for bioinformatics analysis

In the current bioinformatics landscape, where R-centric and Python-centric ecosystems coexist and overlap, there is an increasing demand for the organic integration of these disparate development environments. As bioinformatics practices become ubiquitous, it is crucial to lower the technical barriers for biologists to adopt software engineering standards--such as version control, environment reproducibility, code readability, continuous integration/continuous deployment (CI/CD), and comprehensive documentation--which often present significant implementation hurdles for biologists with limited programming experience. To address these challenges, we developed BasalCell (https://github.com/yo-aka-gene/BasalCell), a project scaffolding system designed to provide a standardized, easily reproducible template that integrates these essential features by default--enabling researchers to seamlessly manage multi-language environments and automate rigorous development workflows, ultimately fostering greater transparency and reliability in biological data science.

bioinformatics↗

bioRxiv2026

Design-space requirements for abundance-amplified drug-like targeting of RHSVV/PAb240-like p53 exposure in TP53-mutant cancer

Mutant p53 accumulation is established, but whether abundance can complement conditional RHSVV/PAb240-like exposure depends on the trade-off between target coverage and normal-tissue separation. We analyzed 809 tumors and 523 organ-matched adjacent-normal specimens from eight CPTAC cohorts. The 67.5% high-p53 fraction among quantified DNA-binding-domain missense tumors and the 2.59-fold paired tumor/normal median were treated only as dataset-specific secondary calibration. The design pool comprised 316 annotation-compatible missense tumors; 268 had quantified p53. Eligibility retained 179 tumors at cohort-normal P95, 159 at R[≥]2, 90 at R[≥]3, 54 at R[≥]4, 21 at R[≥]6, and 8 at R[≥]8, where R is abundance relative to the cohort-normal median. Normal stress used a prespecified 2.1-fold total-p53 abundance multiplier from a vinculin-normalized, multi-time-point ionizing-radiation study in early-passage wild-type Mdm2+/+ mouse embryonic fibroblasts; this source met all primary-anchor eligibility criteria. Under this anchor and a sample-level exposed-state mixture weight p=0.90, the full-data lowest passing target/background exposure grid point was q=2.00 pooled and q=2.50 worst cohort at P95, versus q=1.25 for both at R[≥]3; R[≥]3 covered 33.6% and is presented as a pragmatic exploratory intermediate, not an optimum. In 500 whole-pipeline resamples, all seven fixed cohorts were evaluable at R[≥]3 in 416 (83.2%); this is an evaluability fraction, not design or treatment success. Separate 0.05-margin-buffered fixed R[≥]3 bootstrap candidates used q=1.50 pooled and q=1.75 worst cohort and met the internal constraints in 678/1,000 pooled resamples and 628/863 evaluable worst-cohort resamples (628/1,000 overall; 137 were not cohort-evaluable). These post-selection internal sampling audits are neither therapeutic probabilities nor validation. The principal result is an experiment-anchored coverage-q frontier specifying conditional experimental requirements; native RHSVV exposure, tumor killing, and safety remain unmeasured.

cancer biology↗

bioRxiv2026

Acute Exposure to Perfluorooctanoic Acid (PFOA) During Cardiomyogenesis disrupts Transcriptional and Electrophysiological Profiles in Differentiated Myocytes

The early developmental environment plays a critical role in the etiology of cardiovascular diseases (CVDs), but underlying molecular mechanisms are poorly understood. Exposure to per and polyfluoroalkyl substances (PFAS) are linked to various CVDs, but effects of developmental PFAS exposures on the human heart remain unclear. Using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), the objective of this study was to investigate the effects of PFAS exposure during cardiac differentiation on gene expression and function of cardiomyocytes. We exposed two hiPSC lines (one male and one female donor) to perfluorooctanoic acid (PFOA), a common and ubiquitous PFAS (0.05, 0.5, 5, 50, 100, 150, 200 M), followed by assessment of cellular number and pluripotency marker expression. PFOA exposure for 72 hours had no significant effects on hiPSC pluripotency, and modest inhibition of proliferation was observed only at the highest concentration. hiPSCs were then differentiated into ventricular cardiomyocytes in the continued presence or absence of PFOA (0, 0.5, 5, 50 M) using an established small molecules protocol. Optical mapping studies using voltage and calcium-sensitive dyes revealed dose and cell line-specific effects of PFOA on cardiomyocyte voltage and calcium dynamics that were still present 10 days after cessation of exposure. Patch clamping studies demonstrated small but significant reductions in repolarizing IKr currents with 5{micro}M PFOA exposure in cardiomyocytes from both donors. Using RNA-seq, we found that exposure to PFOA led to significant changes in transcriptional pathways related to lipids and lipoproteins in the female hiPSC-CM. In the male hiPSC-CM, we observed significant effects on developmental pathways and calcium homeostasis. Thus, we found that environmentally relevant PFOA exposure during cardiomyocyte differentiation affects the electrophysiological properties and transcriptome of hiPSC-CM even after cessation of exposure, with effects that differ by donor cell line. These findings provide direct experimental evidence that transient developmental exposure to PFOA can durably reprogram human cardiomyocyte function, supporting a developmental origin of PFAS-associated cardiovascular risk. Impact StatementThese studies demonstrate that exposure to environmentally relevant levels of PFOA during the differentiation of hiPSCs into cardiomyocytes alters cardiac gene expression and function, with effects that persist beyond cessation of exposure.

pharmacology and toxicology↗

bioRxiv2026

Chromatin landscape and epigenetic heterogeneity of acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic cancer characterized by proliferation of immature myeloblasts. It shows profound molecular heterogeneity, which has been primarily studied through genetic abnormalities, providing the basis for disease classification, prognostication, and therapeutic choice. However, genetic factors alone may not fully explain AML pathogenesis and diversity, while leaving the role of abnormal epigenome, particularly chromatin state, largely unexplored in a large cohort of patients. Here we show that AML is classified into 16 subgroups with distinct chromatin accessibility profiles based on ATAC-seq in 1,563 AML cases, including novel AML subgroups not previously recognized in conventional genomic classifications. By integrating multi-omics analyses of genome, transcriptome, and major histone marks, we show that these epigenetic subgroups exhibit unique features in clinical presentation, gene mutations, differentiation states, gene expression, and super-enhancer profiles, which are validated across independent cohorts. Single-cell sequencing demonstrates the presence of subgroup-specific ATAC signatures that are shared by all leukemic cells, confirming the definitive role of the epigenome in the ATAC-based classification. Mechanistically, each subgroup is associated with a distinct gene regulatory network centered on key transcription factors, where subgroup-specific super-enhancers play a pivotal role. These ATAC subgroups also have prognostic significance independent of genomic classification, and help reveal unexpected drug sensitivities. In summary, ATAC-based chromatin profiling in this large sample set, combined with multi-omics data, provides new insights into AML pathogenesis beyond genomic profiling and also serves as an invaluable resource for AML research.

cancer biology↗

bioRxiv2026

AtPUP5 functions as a plasma membrane flavin transporter regulating localized riboflavin distribution in Arabidopsis

Riboflavin (vitamin B{square}; RF) and its derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are indispensable cofactors for redox reactions in plants. While higher plants possess a conserved pathway for de novo riboflavin biosynthesis, how flavins are transported and spatially distributed between tissues remains unresolved. In particular, the molecular identity of plasma membrane transporters involved in flavin transport in plants remains largely unknown. Here, we identify Arabidopsis purine permease 5 (AtPUP5) as a plasma membrane-localized protein associated with riboflavin transport and its distribution in plants. Using a riboflavin-auxotrophic yeast mutant, we show that AtPUP5 enhances intracellular accumulation of RF and, to a lesser extent, FMN, whereas FAD accumulation is inefficient under the conditions tested. In planta, AtPUP5 overexpression increases RF accumulation following external application. In contrast, loss-of-function mutants do not display defects in bulk RF uptake at the whole-plant level, indicating that AtPUP5 is not essential for global riboflavin acquisition. Notably, AtPUP5 deficiency results in RF overaccumulation in reproductive organs, including inflorescences, siliques, and seeds, irrespective of external RF supply. This organ-specific phenotype is fully suppressed by genetic complementation and coincides spatially with strong AtPUP5 promoter activity in reproductive tissues. These findings suggest that AtPUP5 contributes to the regulation of localized riboflavin distribution in reproductive tissues. Together, our study provides a molecular framework for plasma membrane-mediated regulation of riboflavin distribution in plants and highlights spatial regulation as an important component of flavin homeostasis.

plant biology↗

bioRxiv2026

A chromatin relay from AIRE to ETS transcription factors sustains peripheral antigen expression in the thymic mimetic cells to ensure central tolerance.

Medullary thymic epithelial cells (mTECs) establish central tolerance by expressing a diverse repertoire of peripheral tissue-specific antigens (TSAs). This diversity is regulated not only by the transcriptional regulator AIRE, but also by lineage-defining factors in tissue-mimetic, AIRE-negative descendants of Aire mTECs (post-Aire mimetic TECs). However, whether and how prior AIRE activity contributes to TSA expression in post-AIRE mimetic TECs remains unclear. Here, we identify the ETS transcription factors, EHF and ELF3, as key regulators that sustain AIRE-primed gene expression in these cells. EHF and ELF3 preferentially bind distal genomic regions which are rendered accessible in advance by AIRE. Combined loss of EHF and ELF3 disrupts expression of AIRE-regulated genes expressed in mimetic TECs, leading to tissue-selective autoimmunity. Our findings reveal a relay mechanism in which AIRE primes chromatin for ETS factors to maintain TSA expression in post-AIRE mimetic TECs, thereby safeguarding self-tolerance.

immunology↗

bioRxiv2025

Two phytohormones synergistically induce parasitic weeds seed germination via KAI2d receptors

Root parasitic plants can severely decrease global crop production. The germination of their seeds is induced by host root-derived strigolactones (SLs). Considering this unique germination system, a "suicidal germination" method has been proposed to control root parasitic plants. However, this method requires the cost-effective production of germination inducers. In this study, we determined that jasmonates and SLs can synergistically induce the seed germination of root parasitic plants (Orobanche minor and Striga hermonthica). Biochemical analyses indicated that jasmonates and SLs cooperatively activate multiple divergent KARRIKIN INSENSITIVE 2 receptors. Our findings have elucidated the host recognition systems associated with these highly duplicated promiscuous receptors, with potential implications for developing a new strategy to protect crops against root parasitic plants.

plant biology↗

bioRxiv2025

Design-of-Experiments for Nonlinear, Multivariate Biology: Rethinking Experimental Design through Perturb-seq

Design of experiments (DOE) principles are increasingly applied to biological assays, yet it remains unclear whether the optimality of their foundational assumption--orthogonal decomposition--holds in nonlinear biological systems. We addressed this question using Perturb-seq as a case study. By benchmarking a design commonly used in Perturb-seq and related experiments against the orthogonal Plackett-Burman (PB) design via simulations, we uncovered a counter-intuitive phenomenon: while orthogonal designs generally excel, the correlated structure inherent to the common design is functionally robust in systems with significant signal amplification. This challenges the blind application of DOE to biology. Based on these findings, we developed the PB suitability index (PBSI), a simple, parameter-free metric that predicts the optimal design solely from network structure. Our work not only provides practical guidelines for Perturb-seq but also establishes a "biology-oriented DOE" framework, bridging the gap between statistical rigor and biological complexity.

bioinformatics↗

bioRxiv2025

Genome editing of the flavanone 3-hydroxylase gene produces a green Perilla line with elevated luteolin accumulation

Perilla frutescens var. crispa is widely cultivated in East Asia and produces a diverse range of secondary metabolites with nutritional and medicinal value. Based on anthocyanin content, perilla is classified into red and green chemotypes. The anthocyanin biosynthetic pathway is highly conserved among plants, and the flavanone 3-hydroxylase gene (F3H) in red perilla is considered essential for this pathway. Here, we used CRISPR-Cas9 genome editing to generate novel Perilla lines with altered metabolite profiles. In four edited T plants, multiple biallelic indels, including a -3 bp in-frame deletion, were introduced at the target site. In the T generation, these mutations and the transgene segregated in a Mendelian manner, resulting in recovery of null-segregant plants. Metabolite analysis revealed strong suppression of anthocyanin biosynthesis and a significant increase in luteolin accumulation in edited lines compared with the wild type. Transcriptome analysis further confirmed the loss of F3H function, demonstrating a metabolic shift of the flavonoid pathway toward luteolin production. This study provides the first functional validation of F3H in perilla and highlights its potential application in breeding cultivars with controlled bioactive compound contents. Our findings also demonstrate practical strategies for implementing genome editing in non-model crops and developing high-value functional cultivars. Practitioner PointsO_LIEditing a single flavonoid biosynthetic gene (F3H) effectively alters pigment composition in perilla leaves. C_LIO_LIIncreased accumulation of luteolin-related compounds suggests potential for enhancing functional metabolites without complex pathway engineering. C_LIO_LIGenome editing offers a feasible tool for perilla improvement in breeding and functional food development. C_LI

plant biology↗

bioRxiv2025

Self-Supervised Missing Wedge Correction in Soft X-Ray Tomography: Towards Accurate Cellular Morphology and Volume Quantification

Soft X-Ray tomography (SXT) is a non-invasive bio-imaging technique that enables 3D imaging of cellular structures in large volume, with a unique resolution range that bridges the gap between fluorescence and transmission electron microscopy. However, a fundamental limitation, the missing wedge artefact caused by incomplete tilt-series acquisition, introduces systematic structural elongation in the reconstructed tomograms. This artifact compromises accurate quantitative biological analysis by overestimating cellular and organelle volumes. To overcome this persistent issue, we introduce a novel, self-supervised missing wedge correction model that learns key sine-wave patterns from existing SXT sinograms of the tilt series stacks. This model can be applied to recover the missing-angle region of the sinogram, reducing distortions and elongations in the reconstructed tomograms. We demonstrate a significant quantitative improvement in artifact removal, achieving faithful recovery of the spherical morphology of lipid droplets. We further applied this method to Plasmodium falciparum hemozoin crystals, a biomarker in antimalarial drug efficacy studies. Our model successfully reduced volume overestimation, achieving up to a 16% decrease in distorted volume. This level of precision is paramount for correctly interpreting the mode of action of antimalarial drugs.

cell biology↗

bioRxiv2025

Graph topology reframes the coherence of cell-state manifold inference under heterogeneous single-cell observations

Manifold-based single-cell omics analyses assume that high-dimensional observations can fall into a low-dimensional space encoding biological constraints. In practice, per-cell observation is highly heterogeneous: shallowly- and deeply-observed cells coexist. In an empirical scRNA-seq dataset, shallowly-observed cells cluster together to generate spurious hubs that can give rise to illusory loops in low-dimensional manifold skeletons in graph abstraction. Several imputation methods leave these artifacts largely intact, whereas graph abstraction restricted to homogeneously-observed cells alone recovers tree-like structures locally representing constrained cell state transitions. Simulations further demonstrate that realistic heterogeneous observation can create spurious subclusters and false branching. Grounded by these observations, we propose topological stability descriptors of low-dimensional manifold skeletons to delineate a regime in which manifold-based inference is trustworthy despite realistic heterogeneous observations. Our findings underscore that the heterogeneity of observations is not merely noise but a source of systemic distortion in manifold-based inference that must be addressed.

bioinformatics↗

bioRxiv2025

NADPH phosphatase activity of Mesh1 controls sleep in Drosophila

Recent findings have shown that metazoans accumulate the bacterial second messenger guanosine tetraphosphate (ppGpp) and possess Mesh1, a gene encoding a ppGpp hydrolase domain. Mesh1 deficiency affects sleep behavior and eclosion under starvation in Drosopila, and ferroptosis in human cells. However, human Mesh1 also exhibits NADPH/NADP+ phosphatase activity in vitro, making it unclear whether these phenotypes result from loss of ppGpp hydrolysis, NADPH/NADP+ dephosphorylation, or both. To address this, we performed biochemical and genetic analysis of Drosophila Mesh1. We first found that Drosophila Mesh1 dephosphorylates NADPH, but not NADP+, in vitro. We subsequently sought to generate Drosophila Mesh1 point mutants specifically impaired in NADPH phosphatase activity. Based on structural data, we mutated W138 and R142, residues that are predicted to interact with NADPH but not ppGpp. W138 was replaced with phenylalanine results in complete loss of NADPH phosphatase activity with retained ppGpp hydrolase activity. Flies carrying the W138F mutation, introduced via genome editing, exhibited shortened total sleep and increased sleep fragmentation in behavioral assays, without changes in intracellular ppGpp levels. These results indicate that the NADPH phosphatase activity of Mesh1, and specifically the W138 residue, is essential for normal sleep regulation in Drosophila.

molecular biology↗

bioRxiv2025

In Vitro Dynamic and Quantitative Monitoring of Strigolactone-signaling Complex Formation by Time-resolved FRET

SummaryStrigolactones (SLs) are a class of plant hormones that play a critical role in the suppression of shoot branching. Furthermore, they are exuded from roots and act as signaling molecules for inter-organism communication in the rhizosphere. Strigolactones trigger those responses by inducing protein-protein interactions (PPIs) of signaling components and subsequent proteolysis of transcriptional repressors. The sequential event involves SL hydrolysis mediated by SL receptors belonging to an /-hydrolase family, although the physiological role of SL hydrolysis is a subject of debate. To date, SL-induced PPIs have been analyzed by methods such as yeast-two hybrid, pull-down, and AlphaScreen assays. However, the kinetic aspect of PPI profiles has not been well studied. Here, we developed an in vitro method to monitor the formation of the SL signaling complex based on Time-Resolved Forster Resonance Energy Transfer (TR-FRET) technology. Our TR-FRET-based assay system allows us to analyze the mode of action of SL analogs from kinetic and quantitative perspectives. Notably, our method revealed differences in the intensity and time-dependency of PPI signals among different SL analogs with a range of hydrolyzabilities. In addition, we found that tolfenamic acid, an antagonist of the SL receptor, inhibited the SL-induced PPI but could not disrupt the already-formed signaling complex. The TR-FRET system was also used to rapidly and specifically detect naturally occurring SLs from root exudates containing many impurities. This work provides insights into the molecular mechanism of SL perception as well as a powerful tool for activity-based screening of SL signaling modulators. Significance statementThe dual roles of strigolactone (SL) receptors in both the perception and deactivation of SLs make it difficult to elucidate the underlying molecular mechanism of SL signaling. We developed a new in vitro method to evaluate the dynamic activation of the SL receptor, and used it to gain deeper insights into the molecular mechanism of SL-signaling complex formation in response to the SL receptor agonists.

plant biology↗

bioRxiv2025

Radiation dose effects in correlative X-ray / cryo-electron microscopy of frozen hydrated biological samples

In cryo-electron microscopy (cryo-EM), imaging of biological specimens is restricted by the limited field of view and by sample thickness. Hard X-ray imaging, with its ability to penetrate samples several tens of micrometers thick, offers a complementary approach for high-resolution visualization. A major concern is whether cryo-preserved samples can withstand the handling conditions at synchrotron facilities without excessive icing, and whether the radiation exposure during X-ray imaging compromises specimen integrity, thereby hindering subsequent attempts to achieve high-resolution 3D reconstructions via cryo-EM. To evaluate this, we deposited apoferritin samples on a cryo-EM grid, exposed them to varied X-ray doses typical for X-ray tomography experiments at a synchrotron facility, and subsequently analysed the exposed particles by cryo-EM. Despite the apparent damage sustained throughout the experiment, the samples remained amenable to cryo-EM analysis, with structural details at a resolution of [~]4 [A] at the highest absorbed X-ray dose of 100 MGy. By comparison, a similar cryo-EM dataset of the apoferritin particles that were not exposed to X-rays but were mounted on the same cryo-EM grid, resulted in a 3D reconstruction at 3.17 [A] resolution. Thus, while radiation damage may limit the high-resolution information in specimens processed by cryo-X-ray tomography, the cryo-preserved biological material exposed to these high X-ray doses can be still used for subsequent cryo-EM workflows aiming to obtain structural biology insights at intermediate to high resolution. These findings lay the groundwork for an integrated imaging workflow that combines X-ray and cryo-EM techniques to enable multiscale analysis of thick vitrified biological specimens.

biophysics↗

bioRxiv2025

Pharmacological potentiation of Nav1.1 channels in interneurons mitigates tau depositions and neuronal death in a mouse model of neurodegenerative dementias

Epileptiform discharges and neuronal hyperexcitability are key pathophysiological features of Alzheimers disease and related tauopathies. We previously identified selective dynfuntion of parvalbumin-positive GABAergic interneurons (PV neurons), which regulate neural network excitability, in a tauopathy mouse model. However, the mechanistic link between PV neuron deficits, tau pathology, and neurodegeneration remains unclear. Here, we demonstrate that pharmacological enhancement of phasic PV neuron activity markedly attenuates tau accumulation and neuronal loss in a tauopathy mouse model. We developed DSR-143630, a novel activator of voltage-gated sodium channel Nav1.1, selectively expressed in PV neurons. Administration of DSR-143630 alleviated febrile seizures in Nav1.1 haploinsufficient mice and suppressed high-frequency oscillations (HFOs), an electrophysiological signature of hyperexcitability associated with cognitive impairments, in rTg4510 tau transgenic mice. Longitudinal tau PET and volumetric MRI demonstrated that DSR-143630 treatment from 4 to 11 months of age profoundly reduced age-dependent tau deposition and atrophy in the neocortex and hippocampus. Postmortem analyses further revealed decreased levels of phosphorylated tau, preservation of neuronal populations, and attenuated neuroinflammatory responses, including reactive gliosis. These findings establish PV neuron dysfunctions and consequent network hyperexcitability as key drivers of tau pathogenesis and highlight pharmacological Nav1.1 activation as a promising disease-modifying strategy for neurodegenerative tauopathies. One Sentence SummaryPharmacological potentiation of interneuronal activities attenuates aberrant network excitability, progressive tau deposition, and neurodegeneration.

neuroscience↗