Biology subjects

Yang, X.

Publications and source records attributed to Yang, X..

At least 181 records · Page 10Linked to original sources

bioRxiv2025

Multimodal Data Fusion Reveals Morpho-Genetic Variations in Human Cortical Neurons Associated with Tumor Infiltration

We introduce LetsACT (Light-Electron-Transcriptome synergistic ACTomography), a multimodal integration platform that overcomes the limitations of single-modality data acquisition and analysis of human brain cells while synergistically leveraging the strengths of each modality. Our approach enables the rapid sample preparation, cell injection, imaging, and multimodal integration of large-scale human neuronal datasets at single-cell resolution. By generating initial laser-scanning-microscopy based optical reconstruction of neuron morphologies followed by refining them using electron-microscopy derived morphological priors, we have assembled one of the largest human cortical morphology datasets to date: 8,398 neurons from 58 donors, with high cortical coverage. This platform is then applied to studying morphological impact of tumor infiltration. Pyramidal neurons in glioma-infiltrated tissues display clear volume shrinkage in somas and branches, tapering from the soma to nearby dendritic compartments. By integrating these morphological variations with spatial and bulk transcriptomic profiles, we find that glioblastoma tissues exhibit dysregulation of 15.29% of genes, including overexpression of TERT, whereas infiltrated tissues show 7.74% gene dysregulation, characterized by overexpression of tumor suppressors such as CDKN2A and TP53. Our analysis implies that pyramidal neurons observed in these infiltrated tissues may involve an active defense instead of undergoing passive apoptosis. Our finding also indicates that LetsACT establishes a valuable resource for the large-scale, comprehensive morpho-genetic analysis of human tissues.

neuroscience↗

bioRxiv2025

Metal-Triggered Rheological Switching in Engineered Lanmodulin Condensates

Reliable recovery of rare earth elements (REEs) is increasingly important for energy and communication technologies, yet current separation methods rely on harsh chemistries and are difficult to scale sustainably. Biological strategies offer a promising alternative but typically require immobilized proteins, introducing diffusion limitations and regeneration challenges. Here, we engineer a phase-separating variant of the high-affinity lanthanide-binding protein Lanmodulin (LanM) by fusing it to an encapsulation peptide (EP) microdomain. The resulting chimera, EP-LanM, undergoes liquid-liquid phase separation upon REE binding, forming condensates whose formation and dynamic properties are governed by metal stoichiometry and temperature. These condensates enable selective capture and release of La3 and Nd3 and support efficient recovery and reuse of the protein. Our findings show that metal-triggered protein condensation can be harnessed as an aqueous, reversible mechanism for REE enrichment, establishing a generalizable biophysical approach for designing functional phase-separating proteins for selective metal separation.

biophysics↗

bioRxiv2025

Identifying High-Dimensional Genomic Factors Modulating Biological Networks Across Multi-Omics Data

Biological traits such as genes, metabolites, and microbial taxa interact within complex networks, yet how genomic factors shape these interactions remains poorly understood. Here, we introduce GFBioNet, a computationally efficient method for identifying factors that modulate direct associations between biological traits within network models. Our two-stage strategy first estimates a baseline network using Gaussian graphical models and then tests whether genomic factors modulate specific network edges (trait-trait relationships), enabling scalable analysis of high-dimensional multi-omics data while explicitly controlling the false discovery rate (FDR). Simulations demonstrate reliable FDR control and high statistical power across a broad range of settings. Applied to multiple datasets, GFBioNet reveals host genetic variants influencing oral microbiome relationships, gut microbial taxa modulating metabolite networks in colorectal cancer, and somatic mutations and copy-number alterations reshaping gene expression networks in lung adenocarcinoma. By expanding network analysis to evaluate modifiers of trait-trait relationships, GFBioNet offers a versatile tool for uncovering the genomic architecture of biological networks across multi-omics studies.

genomics↗

bioRxiv2025

Reciprocal Homoeologous Replacement of MYB Factors Drives the Evolutionary Trade-off between Yield and Fiber Quality in Cotton

The long-standing phenotypic trade-off between Upland cotton (Gossypium hirsutum, high yield) and Sea Island cotton (G. barbadense, high quality) represents a major bottleneck in cotton breeding and industrialization. Despite rapid advances in genomics, the genomic structural variations driving the divergence of these two domestication strategies, and their subsequent impact on downstream transcriptional networks, remain unclear. This study integrates multi-tissue transcriptomic atlases spanning the full growth period with pan-genomic analyses of both Upland and Sea Island cotton, proposing a "Reciprocal Selective Retention (RSR)" strategy adopted by the two species during evolution. Transcriptomic analysis revealed that while the transcriptional chassis of the two species is highly conserved, a drastic "phase inversion" occurs during fiber development. Sea Island cotton appears to trade off for quality by specifically activating a "delayed elongation" module (at 20 DPA), whereas Upland cotton initiates a "precocious filling" program to pursue yield. Further Weighted Gene Co-expression Network Analysis (WGCNA), combined with genomic Presence/Absence Variation (PAV) analysis, identified a set of key transcription factors exhibiting a "3-vs-3" reciprocal loss pattern. Upland cotton specifically retained CRF10, WIND1, and MYB93, constructing a genetic foundation of "robust root system and strong regeneration" to support high yield. Conversely, Sea Island cotton specifically retained MYB111 and ERF105/017 to maintain long-staple characteristics and environmental buffering. Whole-genome structural variation and microsynteny analyses confirmed that these differences stem from asymmetric physical deletions (e.g., a 5 kb deletion in MYB111) or fragment sequence collapse (e.g., a 15.9 kb sequence divergence in MYB93) on homologous chromosomes. The RSR model proposed in this study not only offers a novel insight into the genetic roots of the negative correlation between yield and quality but also provides clear genomic targets for precision improvement using gene-editing technologies such as CRISPR.

genomics↗

bioRxiv2025

Mass Spectrometric Determination of Site-Specific O-Acetylation in Rhamnogalacturonan-I Oligomers

O-Acetylation, a common modification in rhamnogalacturonan I (RG-I), is critical for various biological processes, including plant growth, stress responses, and pathogen defense. Precise determination of the degree and specific positions of acetylation is therefore essential. To date, nuclear magnetic resonance (NMR) and tandem mass spectrometry have been employed to identify acetyl positions in pectin oligosaccharides. Although NMR is effective, it requires pure, high-concentration samples. Tandem mass spectrometry (MS), which uses lower sample amounts, faces challenges due to acetyl migration between monosaccharide positions. The multiple steps in pectin sample analysis can further promote O-acetyl migration, especially near free hydroxyl groups. Moreover, during tandem MS, acetyl groups may detach, complicating accurate tracking. This study presents an approach to lock O-acetyl groups by introducing trideuteroacetyl and propionyl substituents onto free hydroxyls of RG-I or partially acetylated RG-I. By combining matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) MS and electrospray ionization (ESI) MS with MS/MS or tandem mass spectrometry (MSn), we devised a way to determine the monosaccharide sequence in the oligomer and precise positions of acetyl groups in partially acetylated RG-I. This method enables the study of the regiospecificity of recombinant pectin O-acetyltransferases and can be applied to other oligosaccharides to determine acyl positions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/694011v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1384347org.highwire.dtl.DTLVardef@c8f21forg.highwire.dtl.DTLVardef@8fed52org.highwire.dtl.DTLVardef@125c4a1_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

Small Molecule Degradation of the microRNA-21 Precursor Rescues Pathogenic Pathways in Cellular Models of Fibrosis

MicroRNAs (miRNAs) are short RNA molecules that bind to target mRNAs, resulting in translational repression and gene silencing. Overexpression of microRNA-21 (miR-21) is associated with various human diseases, including autosomal dominant polycystic kidney disease (ADPKD) and pulmonary fibrosis. In this study, a previously described heterobifunctional molecule, TGP-21-RiboTAC, that degrades the miR-21 precursor (pre-miR-21) in triple negative breast cancer cells was investigated in polycystic kidney cell lines and a lung fibroblast cell line. In the former, TGP-21-RiboTAC degraded pre-miR-21 and de-repressed of miR-21s downstream target, Programmed Cell Death 4 (PDCD4) and Peroxisome Proliferator-Activated Receptor alpha (PPAR), known drivers of ADPKD. The heterobifunctional molecule also inhibited cyst growth and rescued the metabolic alterations that occur in ADPKD. In the lung fibroblast cell line, MRC-5, TGP-21-RiboTAC also reduced pre- and mature miR-21 levels, rescued Transforming Growth Factor {beta} (TGF-{beta})-induced repression of SMAD Family Member 7 (SMAD7) and inhibited cell invasion. Collectively, these studies demonstrate the potential of targeted RNA degradation as therapeutic agents that retard the development of organ fibrosis.

biochemistry↗

bioRxiv2025

Relative contribution of gonads and sex chromosomes to sex differences in cell-type gene expression in the mouse medial septum and sex-biased disease risk

BackgroundWhile sex differences in the brain have traditionally been attributed to gonadal hormones, emerging evidence points to regulation by sex chromosomes. This study aims to differentiate the influence of gonads versus sex chromosomes on cellular gene expression in the mouse medial septum (MS), a critically understudied brain region. MethodsUsing single nucleus RNA-sequencing and the Sex Chromosome Trisomy mouse model, we (1) quantified sex differences in cellular gene expression and (2) isolated sex-biasing effects by identifying perturbed cell types, differentially expressed genes, biological pathways, and gene networks, which were integrated with GWAS data to explore links with sex-biased human phenotypes. ResultsOur analysis revealed that volumetric sex differences in the MS are mirrored by widespread transcriptomic changes across cell types. Critically, genetic effects displayed elevated relevance compared to sex hormones in driving sex-biased gene expression. These effects converge to regulate synaptic/neuronal development, transcriptional regulation, and cellular metabolism. Sex chromosome-associated DEGs were enriched for various human disorders, suggesting a cellular and mechanistic basis for their sex-biased patterns. ConclusionsOur findings challenge the classical gonad-centric views of sexual differentiation, as the MS displays sex-biased transcriptional regulation driven by sex chromosome-associated effects that are highly relevant for human health.

neuroscience↗

bioRxiv2025

Discovery of the TGCB microprotein translated from the lncRNA CHASERR

Long noncoding RNAs (lncRNAs) are key regulators of gene expression, and an increasing number have been found to contain small open reading frames (smORFs) that can be translated into functional microproteins. CHASERR is a conserved cis-regulatory lncRNA positioned upstream of CHD2, where it fine-tunes CHD2 dosage. Deletions spanning the CHASERR gene were recently identified in children with a syndromic, early-onset neurodevelopmental disorder, underscoring the clinical importance of this regulatory locus. Here, we report that CHASERR is not strictly noncoding but encodes a previously unannotated 41-amino-acid microprotein, which we name TGCB. Integrative analyses of bulk and single-cell transcriptomics, 47 public Ribo-seq datasets, coding-potential predictors, and multispecies alignments support active translation and evolutionary constraint of the TGCB smORF. Public mass-spectrometry data provide reproducible peptide-spectrum matches corresponding to its N-terminal region, and immunofluorescence confirms nuclear and cytoplasmic localization. Structural prediction reveals a compact -helical microdomain flanked by intrinsically disordered regions, characteristic of regulatory microproteins. Notably, all pathogenic deletions affecting the CHASERR-CHD2 region remove the entire TGCB coding sequence, raising the possibility that loss of this microprotein contributes to the associated neurodevelopmental phenotypes. These findings position CHASERR as a bifunctional transcript and uncover a conserved microprotein embedded within a clinically relevant regulatory locus.

molecular biology↗

bioRxiv2025

Hyperintense signals in cerebral blood flow maps acquired with pseudo-continuous arterial spin labeling MRI in mice

Background and PurposePseudo-continuous arterial spin labeling (pCASL) MRI is a widely used, noninvasive, contrast-agent-free technique for measuring cerebral blood flow (CBF) and assessing vascular dysfunction across diverse clinical settings and murine disease models. In practice, arterial-transit artifacts that generate hyperintense signal in CBF maps warrant careful consideration. While these effects are well characterized in humans, they are less well understood in mice owing to the marked interspecies physiological differences. MethodsTo address this knowledge gap, we systematically characterized pCASL hyperintense signal as a function of post-labeling delay (PLD) and crusher-gradient strength in mice. Numerical simulations were also performed to validate the experimental findings. ResultsWe found that hyperintense signals in mice extend to arteries, major veins, and ventricular structures (e.g., choroid plexus). Such a pattern was different from human pCASL images, where hyperintense signals are predominantly present in arteries. Statistical analyses supported a PLD of 500 ms as a pragmatic balance between detection sensitivity and suppression of vascular contamination. Additional experiments and numerical simulations showed that, within the tested range, stronger crusher gradients provided little extra vascular suppression--primarily because large vessel calibers relative to small voxels limit intravoxel phase dispersion. These findings refine the interpretation of murine pCASL signals and facilitate more accurate perfusion imaging in preclinical pathophysiological studies.

bioengineering↗

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

Dorsomedial hypothalamus cold-sensitive neurons drive shivering thermogenesis

Hypothermia, a decline in core body temperature below 35{degrees}C in homeotherms, elicits rapid, asynchronous involuntary shivering thermogenesis; however, the hypothalamic neurons responsible for initiating this response remain uncharacterized. Here, retrograde transsynaptic tracing combined with RNA-seq identified a distinct population of VGLUT2-positive neurons enriched with Calbindin D28k (CALB1) within the dorsomedial hypothalamic nucleus (DMHCalb1/Vglut2). Convergent evidence from chemogenetic, optogenetic, fiber photometry calcium imaging, and electromyography (EMG) experiments demonstrated that these neurons selectively mediate hypothermia-triggered shivering thermogenesis. Bidirectional perturbation of DMHCalb1/Vglut2 activity modulated shivering intensity, while CALB1-negative VGLUT2-expressing DMH neurons were responsible for non-shivering thermogenesis (NST). Genetic ablation of afferent inputs from LSI/POA/VLPAG projecting to DMHCalb1/Vglut2, as well as ex vivo pharmacological synaptic blockade, failed to eliminate shivering responses during hypothermia, indicating that their activation is independent of canonical cold-responsive circuits. Hypothermia significantly suppressed transient A-type K (IA) currents, without affecting delayed rectifier K (IK) currents, accompanied by a pronounced reduction in the IA inactivation time constant relative to normothermic 36 {degrees}C. Collectively, hypothermia elevates DMHCalb1/Vglut2 excitability through IA-dependent reshaping of action potential dynamics. Shortened action potential repolarization and afterhyperpolarization duration cooperatively boost neuronal firing, constituting an intrinsic mechanism for DMHCalb1/Vglut2 neuron-driven shivering initiation.

neuroscience↗

bioRxiv2025

Antibacterial Activity of the Natural Product Elaiophylin against Streptococcus suis and its Biofilm Eradication Effect

The multidrug resistance (MDR) problem in Streptococcus suis(S. suis) is becoming increasingly severe, necessitating the development of novel antibacterial agents and strategies. In this study, seven Elaiophylin derivatives were isolated from Streptomyces sp. WS-30248, and the antibacterial activity and mechanism of action of the principal compound, Elaiophylin, against S. suis were systematically evaluated for the first time. Through comprehensive approaches including in vitro efficacy assays, biofilm inhibition and eradication tests, bacterial membrane integrity analysis, reactive oxygen species (ROS) level detection, and a mouse infection model, Elaiophylin was found to exhibit significant antibacterial activity against multiple clinically MDR S. suis strains. Its minimum inhibitory concentration (MIC) was as low as 0.5 g/mL, and complete bactericidal activity was achieved within 24 hours at 4xMIC. The compound effectively inhibited and eradicated bacterial biofilms, directly killing embedded cells within the biofilm matrix. Mechanistic studies revealed that Elaiophylin functions through multiple synergistic pathways, including disruption of bacterial membrane integrity and induction of massive ROS accumulation, thereby interfering with the proton motive force (PMF), depleting intracellular ATP, and blocking energy metabolism. In the mouse infection model, the Elaiophylin-treated group showed a significantly increased survival rate of 60% and effectively reduced bacterial loads in tissues. This study demonstrates that Elaiophylin is a highly promising natural candidate drug with multi-target synergistic effects, offering a new strategy to combat MDR S. suis and biofilm-associated infections.

microbiology↗

bioRxiv2025

LorMe: a streamlined and interoperable R framework for end-to-end microbiome analysis

Microbiome research is rapidly evolving accompanied by increasingly diverse analytical strategies and visualization formats. However, existing R-based tools remain fragmented, differ in data structures, and often require extensive package-specific pre-processing. This increases command-line complexity and limits both interoperability and reproducibility across packages. Here, we present LorMe (Lightweight One-line Resolving Microbial Ecology), an R package that provides a unified, interoperable, and user-friendly framework for microbiome data analysis. LorMe incorporates a standardized S4 object system with fully bidirectional compatibility with phyloseq and microeco, which enables seamless data exchange across major microbial analysis packages. A global configuration system ensures consistent parameter control and visualization standards, and a modular architecture supports both complete end-to-end workflows and flexible execution of individual analytical components. Based on these, LorMe further offers an one-command pipeline that conducts the full spectrum of microbial community analyses, including alpha and beta diversity, differential abundance testing, co-occurrence network inference, and meta-network construction, while archiving all intermediate objects and source data to ensure complete reproducibility. Demonstrations using sample datasets show that LorMe performs comprehensive analyses within minute, produces publication-ready outputs, and maintains methodological transparency. Application to a real rhizosphere dataset revealed biologically coherent patterns across diversity metrics, differential taxa, and network modules, highlighting the capacity of LorMe to support robust ecological interpretation. Collectively, LorMe provides a lightweight, extensible, and flexible solution that reduces technical barriers and enhances reproducibility in microbiome research. LorMe package is freely accessible from both CRAN (https://cran.r-project.org/web/packages/LorMe) and github (https://github.com/wangnq111/LorMe)

bioinformatics↗

bioRxiv2025

Fluctuating flooding motivates the facilitation of a wetland invader: a probe into the stress gradient hypothesis

Stress gradient hypothesis proposes that the plant interaction tends to convert from competition to facilitation when facing accelerating stress. The present study aims to explore the interaction between two co-existing wetland plant invaders - Alternanthera philoxeroides and Myriophyllum aquaticum with exposure to flooding stress. Different plant assemblages including monospecific (single individual per species), homospecific (two individuals of same species) and heterospecific (two individuals of different species) treatments were subjected to different flooding regimes including mesic habitat, constant flooding and fluctuating flooding. The plant interaction was evaluated by biomass accumulation, biomass allocation and relative competition intensity index (RCI). We found that the biomass accumulation and allocation of A. philoxeroides were consistent across different treatments of community assemblage and flooding regime, while the root mass, biomass and root mass allocation of M. aquaticum significantly increased at the presence of A. philoxeroides. Moreover, the RCI of M. aquaticum decreased at the presence of A. philoxeroides. Especially, the RCI of M. aquaticum was 0.06 in the homospecific community, while that of M. aquaticum was -0.82 in the heterospecific treatment under fluctuating flooding condition. Overall, Alternanthera philoxeroides facilitated M. aquaticum, especially under fluctuating flooding condition, which complies with the stress gradient hypothesis. The water level drawdown can benefit the impedance of the growth of M. aquaticum and the deceleration of the co-invasion of A. philoxeroides and M. aquaticum.

ecology↗

bioRxiv2025

Single-Cell Multi-Omics Dissects Transcript Isoform and Immune Repertoire Dynamics in Human Immunosenescence

Immunosenescence, a major hallmark of systemic aging, refers to the progressive functional decline of the immune system. This decline not only compromises host defense and immunological memory but also fuels chronic inflammation and tissue degeneration (collectively known as inflammaging). While single-cell RNA sequencing (scRNA-seq) has revealed transcriptomic alterations in immune aging, analyses restricted to transcript abundance fail to capture deeper regulatory layers, such as transcript isoform diversity and the remodeling of immune receptor repertoires. To address this, we present the human peripheral immune single-cell multi-omics atlas that integrates gene expression, transcript isoforms diversity, and immune receptor repertoires. By combining single-cell full-length transcriptome sequencing (scCycloneSEQ), short-read scRNA-seq, and single-cell immune receptor sequencing (scTCR/BCR-seq), we systematically profiled peripheral blood mononuclear cells (PBMCs) from healthy young and elderly donors. Our analyses uncovered extensive age-related remodeling of immune cell composition, functional states, and TCR/BCR diversity. Notably, we identified in CD4 effector memory T cells exhibited widespread differential isoform usage (DIU), 3'UTR length variation, and a marked reshaping of cytotoxic T lymphocyte (CTL) clonotypes--all closely associated with aging-related inflammation and cellular senescence. This multi-omics atlas delineates key molecular features of immunosenescence and provides a high-resolution resource for deciphering the regulatory architecture underlying immune aging.

immunology↗

bioRxiv2025

Hidden-driver inference reveals synergistic brain-penetrant therapies for medulloblastoma

Effective therapies for high-risk medulloblastoma (MB), particularly MYC-driven Group 3 (G3) MB, remain elusive due to limited druggable mutations, poor blood-brain barrier (BBB) penetration, and rapid resistance. We developed SINBA (Synergy Inference by Data-driven Network-Based Bayesian Analysis), a systems biology framework that computationally prioritizes synergistic, BBB-permeable drug combinations by identifying hidden drivers sustaining oncogenic programs. Integrating MB-specific networks, transcriptomic data, and drug-gene interactions, SINBA nominated 32 candidates, of which 19 were experimentally validated as synergistic. Through iterative prioritization and experimental refinement, the MEK inhibitor mirdametinib and p38 inhibitor regorafenib emerged as the top brain-penetrant pair, suppressing G3 MB progression and extending survival in xenograft and immunocompetent models, with efficacy enhanced by low-dose radiation. Single-cell analysis revealed selective targeting of developmental origins and immune reprogramming. These findings establish SINBA as a computationally assisted discovery framework for clinically actionable combinations in high-risk MB.

cancer biology↗

bioRxiv2025

Scalable Human Cellular Models of Parkinson Disease Reveal A Druggable Link Between the Angiotensin Receptor 1 and Alpha-Synuclein Pathology

BackgroundParkinsons disease (PD) involves progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra. No disease-modifying treatments exist, only symptomatic relief. Our lab reported an unbiased screen in larval zebrafish identifying renin-angiotensin-aldosterone system (RAAS) inhibitors, including clinically used AGTR1 inhibitors for hypertension, as potent neuroprotective agents. This study aims to investigate the effects of AGTR1 inhibition on human mDA neuron survival using inducible neurodegenerative 2D and 3D models for human mDA neuron degeneration. MethodsWe report a scalable high-content platform, using CRISPR-engineered human induced pluripotent stem cell (hiPSC)-derived mDA neurons expressing a tyrosine hydroxylase (TH) fluorescent reporter, allowing to track mDA neuron survival live "in a dish". We developed chemically inducible neurodegenerative 2D and 3D models for human mDA neuron degeneration, allowing to recapitulate PD pathology in human cells in vitro. ResultsOur model establishes scalable human cellular models of PD well-suited for therapeutic discovery. Using 2D and 3D mono and co-cultures, this study demonstrates that inhibition of AGTR1, via chemical or genetic means, protects against chemically induced mDA neuron degeneration. Transcriptomic analyses show AGTR1 inhibition lowers synuclein transcription, by reducing SNCA and SNCB gene expression. In 3D neuron-glia assembloids, AGTR1 inhibition protects against the accumulation of phosphorylated form of -synuclein (p129-Syn), key PD pathological marker. ConclusionsWe highlight AGTR1 as a key regulator of -synuclein transcription and aggregation in human mDA neurons, and AGTR1 inhibition as pro-survival in human iPSC-derived models. These findings position inhibition of AGTR1 as a promising therapeutic strategy for PD neuroprotection.

neuroscience↗

bioRxiv2025

Brain endothelial PRMT5-ANGPTL4 axis regulates cerebellar inhibitory synaptogenesis and motor coordination

Brain vasculature is essential for central nervous system function, but its specific roles in synaptic development and motor function regulation are poorly understood. In this study, we identify a cerebrovascular signaling axis wherein endothelial PRMT5 critically regulates inhibitory synaptogenesis and motor coordination. Cerebrovascular-specific deletion of Prmt5 gene leads to excessive inhibitory synaptic input onto Purkinje cells and progressive motor deficits in mice. Mechanistically, PRMT5 deficiency epigenetically upregulates the expression of the secreted factor ANGPTL4 through reduced symmetric dimethylation of H3R8 and H4R3, along with increased H3K9 acetylation at the Angptl4 promoter, thereby driving excessive inhibitory synaptogenesis onto Purkinje cells. Importantly, Angptl4 deletion in brain endothelium normalizes inhibitory synaptic input onto Purkinje cells and restores motor coordination in PRMT5-deficient mice. Together, these findings define the endothelial PRMT5-ANGPTL4 axis as a key regulator of cerebellar inhibitory circuitry and motor function, highlighting cerebrovascular mechanisms as potential therapeutic targets for motor coordination disorders. Teaser Cerebrovascular PRMT5 prevents excessive inhibitory synaptogenesis via epigenetic repression of Angptl4.

neuroscience↗