Biology subjects

Wong, K.

Publications and source records attributed to Wong, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Phosphoregulation of hierarchical protein condensate formation during clathrin-mediated endocytosis

The sequential assembly of over 50 proteins during clathrin-mediated endocytosis (CME) is well documented in yeast. However, the mechanisms governing this ordered recruitment remain poorly understood. Biomolecular condensation is proposed to orchestrate CME, but defining biophysical parameters in vivo remains challenging. Here, we developed a quantitative in vivo titration strategy to systematically determine CME protein assembly profiles. Beyond the previously reported Ede1 (yeast Eps15), seven additional proteins formed enlarged, concentration-dependent assemblies with distinct biophysical properties. Single-cell profiling revealed two biophysical classes among these eight proteins: homeostatic buffers with defined saturation boundaries and continuous assemblers that scale linearly. Acting as scaffolds and clients, these conserved proteins form an interconnected network of kinases, phosphatase recruiters, and substrates. Within this network, reversible phosphorylation modulates assembly stability to drive recruitment transitions. Collectively, this work establishes a two-stage model of protein condensation that drives CME progression from initiation to maturation and offers a general framework for how protein phosphorylation dynamically modulates biomolecular condensation in vivo.

cell biology↗

bioRxiv2026

A Conserved SIFamide Circuit Functions as the Insect Vagus Nerve

The insect functional homolog of the mammalian vagus nerve has remained elusive. Here, we identify the SIFamide (SIFa) peptidergic circuit as this homolog in Drosophila melanogaster. SIFa neurons project the longest axons from the brain to the hindgut ampulla, forming synapses with peripheral SIFa-receptor (SIFaR) neurons originating in the abdominal ganglion. This circuit is functionally plastic: sexual experience enhances synaptic strength at the hindgut, increasing excretion while reducing mating duration to to favor energy conservation and metabolic recovery. Mechanistically, this shift involves octopaminergic/tyraminergic gating and SIFa-mediated modulation of Adipokinetic Hormone (AKH) from the corpora cardiaca. We further uncover a feedback loop in which SIFaR/Allatostatin-A (AstA) neurons project back to the brain, signaling hindgut physiological status to SIFa neurons via AstA-R1. This hindgut projection is conserved across diverse insect orders. Thus, the SIFa-SIFaR circuit constitutes an evolutionarily conserved "insect vagus nerve" that integrates metabolic state and reproductive history to optimize survival strategies.

neuroscience↗

bioRxiv2026

Fundamentals on the Kinetic and Thermodynamic Analysis of Oligonucleotide DNA Hybridization by Surface Plasmon Resonance: A Guide for HIF1α Antisense Design.

Antisense oligonucleotides (ASO) are nucleotide polymers that hybridize to sense strands and have been successful in treating a variety of diseases. A wide range of strategies have been investigated to optimize and develop ASO for clinical studies. A key objective for this study was to provide an overview of the range of detailed data that get be obtained and provide an updated method review on how to design surface plasmon resonance (SPR) kinetic experiments for DNA oligonucleotide hybridization studies that can also be applied to other ASO including peptide nucleic acids (PNA). We describe many lessons learned from published literature and provide a state-of-the-art strategy and methods for generating not only kinetic but also thermodynamic characterizations of oligonucleotide hybridization. In this study we have performed an SPR kinetic and thermodynamic analysis for the hybridization of HIF1 antisense DNA strands to its immobilized Intron2-Exon3 splice site sense DNA strand to provide insight, in general, on the optimal length and insight into optimal design of DNA ASOs. We provide a process on how to design experiments to: 1.) obtain oligonucleotide-length dependent kinetics, 2.) analyze reactions to obtain association and dissociation rate kinetics (ka, kd), assess if hybridization follows a 2-state model and to obtain kinetic dissociation constants (Kd), 3.) perform temperature-dependent hybridization kinetics to obtain thermodynamic values ({Delta}H{degrees}, {Delta}S{degrees} and {Delta}G{degrees}) that can give insight into the molecular interactions driving hybridization, 4.) compare experimental thermodynamic values to values derived from nearest-neighbor prediction models to identify atypical reactions and importantly 5.) enable calculations to predict oligomer hybridization affinity at the physiological 37 {degrees}C temperature to asses if the design of the oligomer will have the required cellular activity for a therapeutic effect. The strategy and results presented throughout the paper are compared to previous SPR reports and suggestions made to optimize kinetic studies.

biochemistry↗

bioRxiv2026

Non-invasive Vagal Nerve Stimulation as a Potential Treatment for Repetitive Blast Trauma

BackgroundPolytrauma caused by exposure to high explosives (blast) is increasingly common among military personnel and civilians yet treatment for related post-concussive symptoms and chronic behavioral dysfunction is limited. Therapeutic targets following these injuries are typically focused on the central nervous system, with less attention placed on potentially more accessible peripheral targets. Vagus nerve stimulation (VNS) has recently gained traction as a potential therapeutic modality but has yet to be examined in a blast trauma setting. MethodsOur well-established blast overpressure model was utilized to induce repetitive (3x) blast trauma, followed by treatment with non-invasive transcutaneous VNS one hour following each blast exposure in male mice. Acutely following repetitive blast exposure, we measured serum and brain cytokine levels, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. Chronically (1-3 months post blast), mice were assessed for behavioral outcomes related to mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD), including acoustic startle (hyperreactivity), probabilistic discounting (risky decision making), and two-bottle choice test (voluntary alcohol consumption). ResultsVNS treatment following blast exposure decreased acute blast-induced inflammatory response in the blood and brain, especially serum IL-9 and IP-10, and brain MPC-1. Chronic behavior tests demonstrated a VNS-dependent reduction in blast-induced risky decision-making and a decreased intake and preference for ethanol. Conversely, VNS was not effective in preventing acute blast effects on the microbiome or chronic hyperreactivity behaviors measured with acoustic startle. DiscussionThis study identifies the vagus nerve as a novel peripheral target for treating acute and chronic blast-induced dysfunction.

neuroscience↗

bioRxiv2026

Deciphering the Multiscale Morphology of Somatic Oncogenic Alterations in Hepatocellular Carcinoma

Somatic oncogenic mutations are typically defined by their molecular alterations, yet how they reorganize cellular architecture within intact tissues remain largely unknown. Here, we demonstrate that distinct oncogenic drivers produce unique multiscale architectural phenotypes that can be quantitatively resolved in intact liver tissue. Using iterative expansion microscopy, multiscale light-sheet imaging, and three-dimensional morphometric analysis, we systematically mapped structural remodeling from single-cell morphology to mitochondrial architecture in mosaic mouse models of hepatocellular oncogene activation. NRAS and CTNNB1 induced fundamentally different morphological programs. NRAS activation drove extensive remodeling of cell morphology, membrane curvature, and surface irregularity, whereas CTNNB1 activation largely preserved global cell morphology while selectively altering mitochondrial organization and shape. We first established a zonation-aware reference state for interpreting oncogene-associated organelle remodeling by resolving mitochondrial differences between periportal and pericentral hepatocytes. Within this framework, CTNNB1 activation shifted mitochondrial features toward a pericentral-like state, consistent with the role of Wnt/{beta}-catenin signaling in hepatic zonation and metabolic identity. Furthermore, integrating cellular morphology, membrane geometry, and mitochondrial architecture improved discrimination of oncogenic states beyond any individual structural feature, demonstrating that mutation-specific phenotypes arise through coordinated remodeling across multiple biological scales. Together, these findings establish multiscale structural phenotyping as a framework for linking oncogenic genotype to three-dimensional cellular organization and reveal that distinct oncogenic drivers remodel different architectural compartments during liver oncogene activation.

cancer biology↗

bioRxiv2026

A multi-organ spatial metabolomic atlas of exercising mice reveals neuronal Complex I as a convergent and sufficient axis for tau pathology reduction in PS19

We constructed a spatially resolved metabolomic atlas of long-term exercise across six major organs in wild-type mice: brain, heart, lung, liver, kidney, and skeletal muscle, cataloguing 224 metabolic features and revealing coordinated inter-organ remodeling. Surprisingly, the brain showed particularly pronounced region-specific adaptation. Because pathological tau associates with synaptic mitochondria from early stages of tauopathy, we extended this multi-organ spatial metabolomic approach to PS19 mice and found that exercise reduced over 70% of observable tau pathology in PS19 hippocampus and restored the mitochondrial-related metabolome. Integrated proteomic and spatial metabolomic analyses identified NADH dehydrogenase Complex I as the convergent node. To test this finding biologically, we expressed the yeast NADH dehydrogenase, Ndi1, in PS19 neurons in the absence of exercise. This increased cerebral antioxidants, restored shuttle-linked metabolites, and reduced tau pathology. Increasing NADH dehydrogenase activity through NDI1 reproduces the core anti-tau and metabolic effects of exercise. These findings provide a molecular mechanism for how exercise may prevent or slow tau pathology accumulation, complementing the human-cohort literature linking exercise to delayed cognitive decline.

neuroscience↗

bioRxiv2026

Metabolic Coherence of the Mouse Brain

The brains metabolic demands are well established, but how metabolism is coordinated across anatomically distinct regions remains poorly understood. Here, using matrix-assisted laser desorption/ionization (MALDI) imaging integrated with the Allen Brain Atlas and optimal transport-based computational analysis, we map the spatial metabolome across twelve major mouse brain divisions. We define an optimal-transport-derived inter-regional metabolite similarity metric and refer to it as metabolic coherence. This structure is largely preserved in an amyloid mouse model of Alzheimers disease despite widespread changes in individual metabolite and lipid levels. Individual metabolites and lipids shift in a coordinated manner across regions, sustaining inter-regional relationships even as absolute levels change in patterns indicative of mitochondrial dysfunction. To test whether the coherence metric is responsive to local intervention, we targeted the left hippocampus of mice from this model via lentiviral shHIF1 knockdown or neuronal AAV-mediated AOX expression. Both interventions were associated with metabolite normalization at the injection site. More importantly, normalization extended across distal regions sharing high metabolic similarity with the hippocampus and was accompanied by improved social memory in a single behavioral assay. Gene modulation and amyloid plaque reduction localized to the injection site.

neuroscience↗

bioRxiv2026

Tumor reactivity assessment using clonal expression (TRACE) reveals tumor reactive CD8+ T cell heterogeneity across solid tumors

1IntroductionTumor infiltrating lymphocytes (TIL) drive the anti-tumor activity of a broad class of immunotherapies. In situ TIL are composed of T cells that recognize tumor antigens (Tumor Reactive T cells, or TRTs) as well as bystander T cells with specificity for other antigens. TRT clonotypes are associated with a unique and tumor-driven exhausted transcriptional state, enabling single-cell RNA sequencing (scRNA-seq)-based predictive models for TRTs using experimentally validated clone labels. MethodsIn this study, a clonotype-level CD8+ TRT classifier (TRACE) was built using an aggregated dataset of validated tumor reactive clonotypes and associated scRNA-seq data from multiple publications that overcomes the limitations of training on a single dataset, donor, or indication. TRACE does not require dataset manipulation for training or prediction, enabling it to be easily applied to new test datasets as they emerge. ResultsTRACE exhibited robust performance on held-out TIL and PBMC clones - achieving a mean Matthews correlation coefficient of 0.84 and F1-score of 0.85 - comparable to or outperforming other TRT prediction methods. We experimentally confirmed the reactivity of TRACE-identified TRT clones by co-culturing engineered, ex vivo expanded TIL with autologous melanoma tumor cell lines. Finally, we applied TRACE to evaluate the frequency of TRT across hundreds of patient samples from multiple tumor atlases spanning lung, colorectal, and pancreatic cancer. TRACE scores were observed to be significantly higher in exhausted CD8 T cells in tumors but not in exhausted cells in normal adjacent or non-cancer samples, suggesting specificity towards identifying tumor-antigen experienced T cells. ConclusionTRACE is a tumor reactivity scoring algorithm released with open model weights that can be applied to tissue or blood single-cell RNAseq datasets. Its application should be of general interest for characterizing the fraction of TRTs in TIL and for establishing correlations with clinical response to immunotherapies.

immunology↗

bioRxiv2026

Chromosome-level genome assembly and annotation of the degu (Octodon degus)

High-quality reference genomes are essential for comparative and functional genomics yet remain unavailable for many emerging model organisms. Here, we report OctDeg2.0, a chromosome-level genome assembly and annotation of the degu (Octodon degus), generated using PacBio HiFi long-read sequencing and Hi-C scaffolding from a single male individual. Octodon degus is of growing interest as a natural animal model for aging and Alzheimers disease research. The 3.4 billion base-pair assembly comprises 28 autosomes and both sex chromosomes, with markedly improved contiguity and completeness over the prior short-read assembly while maintaining high base accuracy. The new assembly provides substantially enhanced gene annotation, clearer resolution of chromatin architecture and cis-regulatory element landscapes, with much improved characterization of repetitive and structurally complex regions, including centromeres and segmental duplications. We present a streamlined and reproducible pipeline for high-resolution de novo genome assembly and gene annotation applicable to other emerging model organisms. This work establishes a robust genomic resource for studying molecular and cellular mechanisms in health and disease in Octodon degus.

genomics↗

bioRxiv2026

Dual-inactivation of Regnase-1 and SOCS1 rewires exhausted CD8+ T cell fate to enhance anti-tumor functionality

The solid tumor microenvironment inhibits the functionality of tumor infiltrating T cells recognizing cognate tumor antigen, driving their differentiation towards terminal exhaustion. Interventions are sought to enhance the anti-tumor functionality of tumor-reactive T cells for clinical benefit. The functional genome regulating CD8+ T cell function against solid tumors was mapped by performing genome-wide, focused, and combination in vivo CRISPR/Cas9 screens using OT1 and PMEL TCR transgenic T cells in B16-OVA, MC38-gp100 and EG7-OVA syngeneic tumor models. The ability of the top single hits and combinations, which include Regnase-1 and SOCS1, to enhance CD8+ T cell anti-tumor function was evaluated in the OT1/B16-OVA model with large and established tumors, the disseminated PMEL/B16F10 tumor model, and in a novel murine TIL syngeneic model. The impact of Regnase-1 and SOCS1 single and dual-inactivation on the differentiation of exhausted CD8+ T cell subsets and on long-term persistent memory following tumor clearance was evaluated in OT1 CD8+ T cells in the B16-OVA model. The impact of single and dual-inactivation of Regnase-1 and SOCS1 on the anti-tumor function of experimental human T cell therapeutics was characterized in CRISPR/Cas9-engineered human TIL derived in vitro and in mesothelin-targeting CAR-Ts in vivo. NF-{kappa}B and cytokine signaling were identified as the top pathways regulating CD8+ T cell anti-tumor function, with Regnase-1 and Suppressor of Cytokine Signaling 1 (SOCS1) the top single and combination edits regulating the accumulation of tumor-specific TCR transgenic CD8+ T cells in syngeneic tumor models. Dual-inactivation of Regnase-1 and SOCS1 cooperated through non-redundant mechanisms to strongly expand intermediate (Texint) and effector (Texeff) exhausted CD8+ T cells within lymphoid tissues and tumor, with CD8+ T cells rewired to display an enhanced effector state and suppressed expression of TOX. Dual-edited persistent T effector memory cells (Tem) were formed following tumor clearance. Lastly, Regnase-1 and SOCS1 inactivation enhanced human Tumor Infiltrating Lymphocyte (TIL) and chimeric antigen receptor T cells (CAR-T) therapy functionality. Collectively, this study systematically mapped pathways regulating CD8+ T cell anti-tumor functionality, with Regnase-1 and SOCS1 dual-inactivation found to maximize anti-tumor function through non-redundant mechanisms.

immunology↗

bioRxiv2026

Codon Deoptimization of Multispecific Biologics Reduces Mispairing During Transient Mammalian Protein Expression

Codon optimization is utilized in biologics design to maximize protein expression. Selecting the host organisms most frequently used codons for each amino acid can significantly enhance recombinant protein expression yields. However, non-optimal codons in mRNA can be critical for functional protein production through inducing pauses in or attenuating protein translation. In our study, we have investigated the effect of deoptimizing serine codons in biologics by shifting them from the five most frequently used codons to the least (TCG). Rare serine codons were strategically inserted into the coding sequences of the constant regions in a trispecific antibody (Protein 1), a bispecific antibody (Protein 2), and multiple non-proprietary bispecific antibodies. We observed that inserting 1-2 rare serine codons within an open reading frame led to expression changes that reduced the formation of mispaired 2x light chain and half-molecule species. Protein purity was drastically increased by incorporating two deoptimized serine codons into a single chain. Notably, we observed a negative correlation between total protein expression yield and final product purity. Taken together, our work demonstrates that incorporation of deoptimized serine codons into a single chain can significantly influence multispecific biologic pairing and enhance final product purity. Our findings align with existing literature showing that rare codon usage modulates translation kinetics and protein folding. Future investigation is warranted to enable a priori identification of the rate-limiting chain in multispecific biologics, thereby guiding strategic codon deoptimization prior to expression.

bioengineering↗

bioRxiv2025

DINOcell: Learning Generalizable Perturbation Effects through Self-Distillation

AO_SCPLOWBSTRACTC_SCPLOWPredicting cellular responses to therapeutics is a promising approach for novel target discovery. However, state-of-the-art computational models designed to predict perturbation effects struggle to generalize and outperform simple baselines. We present DINOcell, a weakly supervised framework that adapts self-distillation to single-cell transcriptomics for predicting perturbation effects. We demonstrate that DINOcell outperforms baselines in predicting the effects of single gene perturbations. Furthermore, DINOcell accurately predicts non-additive effects of combination perturbations, indicating its capacity to model complex genetic interactions. Finally, we show that DINOcell learns representations that capture biological signals and is a promising, generalizable approach for in silico perturbation modeling, providing a valuable tool for accelerating therapeutic target discovery.

bioinformatics↗

bioRxiv2025

Lower Airway Dysbiosis in NTM+ Bronchiectasis is Associated with NET-Predominant Severe Phenotypes

RationaleThe discoveries of neutrophilic inflammation and Pseudomonas-dominant pulmonary dysbiosis have helped pave the way for host-directed therapy in bronchiectasis. Substantial knowledge gaps remain about the interplay between neutrophilic signatures and microbes in non-tuberculous mycobacterial lung disease (NTM-LD), a phenotypically diverse lung infection that is increasingly prevalent in the United States and other parts of the world. ObjectivesEvaluate the lower airway microbiota and neutrophilic traits in NTM- and NTM+ bronchiectasis. Methods16S rRNA gene sequencing, cell counts and neutrophil extracellular trap (NET) immunoassays were performed on bronchoscopic lower airway samples in 200 bronchiectasis subjects (108 NTM-, 92 NTM+). A preclinical model of oral commensal micro-aspiration and NTM infection was used to profile the murine lower airways with flow cytometry and a NET assay. Measurements and Main ResultsLower airways of NTM+ bronchiectasis patients were enriched with Mycobacterium and oral commensals (e.g., Veillonella, Prevotella). NET levels were higher in NTM+ BAL. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine micro-aspiration model, the combination of oral commensals and Mycobacterium led to a sustained pro-inflammatory immune response marked by an increase in Th17, {gamma}8T cells, PD-1+ T lymphocytes as well as higher NET levels. ConclusionsOur analyses showed that distinct microbiome features beyond the primary pathogen can contribute to neutrophilic inflammation and severe disease phenotypes in bronchiectasis/ NTM-LD.

immunology↗

bioRxiv2025

Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer

Autophagy inhibitors are promising compounds to treat pancreatic ductal adenocarcinoma (PDA) but their efficacy in patients is unclear, highlighting a need to understand mechanisms of resistance. We used a novel approach to uncover metabolic adaptations that bypass autophagy inhibition. Utilizing PDA cells with acquired resistance to different autophagy inhibitors, we found that severe autophagy depletion induces metabolic rewiring to sustain TCA intermediates and nucleotides for biosynthesis. Long-term autophagy inhibition results in altered pyruvate metabolism likely regulated by lower pyrimidine pools. Cells adapting to loss of autophagy preferentially salvage pyrimidines to replenish these pools instead of synthesizing them de novo. Exploiting this metabolic vulnerability, we found that acquired resistance to autophagy inhibition promotes increased salvage and therefore sensitivity to pyrimidine analogues, including gemcitabine and trifluridine/tipiracil leading to combinatory effects with autophagy inhibitors and pyrimidine analogs. These studies provide mechanistic insight defining how autophagy inhibition can be leveraged to treat pancreatic cancer.

cancer biology↗

bioRxiv2025

Exploring the association between walking, sleep patterns, brain perivascular spaces, and cognitive function in Parkinson's disease

Perivascular spaces (PVSs) support brain waste clearance and are influenced by sleep. In Parkinsons disease (PD), sleep is often disrupted, and can co-occur with gait dysfunction. This study investigated how sleep disruption, walking difficulties, and cognition relate in PD, considering PVS as a mediator. Our cohort included 348 participants -healthy controls (HC, n=59), prodromal (n=117), and PD patients (n=172)-in the Parkinsons Progression Markers Initiative (PPMI) study. Insomnia and walking issues were assessed by questionnaire, cognition was measured with the Symbol Digit Modalities (SDM) test, and PVS volume fraction in white matter (WM-PVS) and basal ganglia (BG-PVS) was quantified. PVS did not mediate the relationship between sleep or motor problems, on cognition. Walking difficulties were directly linked to poorer cognition, and insomnia to walking deficits. BG-PVS was negatively associated with cognition. PVS burden predicted cognitive function after five years, but not disease progression as indexed by cerebro-spinal fluid (CSF) biomarkers. These findings suggest walking deficits directly relate with cognition in PD, but the relationship is not mediated by PVS.

neuroscience↗

bioRxiv2025

Unveiling Interaction Signatures Across Viral Pathogens through VASCO: Viral Antigen-Antibody Structural COmplex dataset

Viral antigen-antibody (Ag-Ab) interactions shape immune responses, drive pathogen neutralization, and inform vaccine strategies. Understanding their structural basis is crucial for predicting immune recognition, optimizing immunogen design to induce broadly neutralizing antibodies (bnAbs), and developing antiviral therapeutics. However, curated structural benchmarks for viral Ag-Ab interactions remain scarce. To address this, we present VASCO (Viral Antibody-antigen Structural COmplex dataset), a high-resolution, non-redundant collection of [~]1225 viral Ag-Ab complexes sourced from the Protein Data Bank (PDB) and refined via energy minimization. Spanning Coronaviruses, Influenza, Ebola, HIV, and others, VASCO provides a comprehensive structural reference for viral immune recognition. By comparing VASCO against general protein-protein interactions (GPPI), we identify distinct sequence and structural features that define viral Ag-Ab binding. While conventional descriptors show broad similarities across datasets, deeper analyses reveal key sequence-space interactions, secondary structure preferences, and manifold-derived latent features that distinguish viral complexes. These insights highlight the limitations of GPPI-trained predictive models and the need for specialized computational frameworks. VASCO serves as a critical resource for advancing viral immunology, improving predictive modeling, and guiding immunogen design to elicit protective antibody responses. By bridging sequence and structural immunological datasets, VASCO should enable better docking, affinity prediction, and antiviral therapeutic development--key to pandemic preparedness and emerging pathogen response.

biophysics↗

bioRxiv2024

Activation of Wnt/β-catenin signalling by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary gland basal cell adenoma

Wnt signalling must be just right to promote tumour growth. Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Due to their rarity, the genetic profiles of BCA and BCAC have not been extensively explored. Using whole-exome and transcriptome sequencing of BCA and BCAC cohorts, we identify a novel recurrent FBXW11 missense mutation (p.F517S) in BCA, that was mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-function (GoF) mutation. These driver events collectively accounted for 94% of BCAs. In vitro, mutant FBXW11 had a dominant negative affect, characterised by defective binding to {beta}-catenin and the accumulation of {beta}-catenin in cells. This was consistent with the nuclear expression of {beta}-catenin observed in BCA cases harbouring the FBXW11 p.F517S mutation and activation of the Wnt/{beta}-catenin pathway. The genomic profiles of BCAC were distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-{kappa}B signalling pathway genes. A single BCAC, which may represent a malignant transformation of BCA, harboured the recurrent FBXW11 mutation. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities.

cancer biology↗

bioRxiv2024

Positive Allosteric Modulation of the α5-GABAA receptors prevents neuronal atrophy and cognitive decline independently of tau tangle accumulation in the PS19 mouse model

BackgroundDysregulated Tau phosphorylation (p-Tau) is a hallmark of neurodegenerative disorders such as Alzheimers disease (AD) or frontotemporal dementia (FTD), resulting in neurofibrillary tangle accumulation, neuronal atrophy and cognitive impairment. Impaired somatostatin (SST) expression and reduced SST-expressing GABAergic neurons significantly contributes to AD-related pathophysiology and correlates with cognitive impairment. SST+ interneurons inhibit the dendrites of excitatory neurons in cortical layers and hippocampus, primarily through 5-GABA-A receptors, regulating cognitive function. Leveraging a newly developed small molecule that targets the 5-GABA-A receptors via positive allosteric modulation (5-PAM), we assessed its effects on p-Tau-related neuronal morphology, cognitive deficits and protein expression. MethodsIn the PS19 transgenic mouse model, we administered the 5-PAM, GL-II-73, either acutely or chronically at 3 and 6 months, corresponding to early and advanced stage of p-Tau accumulation. Golgi staining analyzed dendritic morphology and spine density in mice chronically exposed to 5-PAM. Western blotting was used to quantify p-tau and Tau expression. Spatial working memory was assessed using the Y-maze. ResultsChronic treatment at 3 and 6 months mitigated p-Tau-induced loss of spine density and reduced dendritic length. 5-PAM treatment did not affect p-tau levels. 5-PAM effectively reversed spatial working memory deficits induced by p-tau accumulation both acutely and chronically. Conclusions5-GABA-A receptor positive allosteric modulation displayed neurotrophic (spine and dendritic pathology) and procognitive (working memory) effects in the PS19 model, independently of p-Tau burden. This suggests a novel therapeutic strategy for p-Tau-related pathologies with both symptomatic and disease-modifying potential.

neuroscience↗