SEARCH · bioRxiv Science

Results for “Pathology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 469 records · Page 26Linked to original sources

bioRxiv2025

Striatal pathology in Spinocerebellar Ataxia Type 1 mice: A comparative study with Huntingtons disease

Spinocerebellar ataxia type 1 (SCA1) and Huntingtons disease (HD), are motor diseases caused by CAG expansions in ATXN1 and HTT, where SCA1 shows prominent cerebellar neurodegeneration and HD shows prominent striatal neurodegeneration, particularly in the Medium Spiny Neurons (MSNs). Since human and mouse studies demonstrate progressive striatal vulnerability in SCA1, we examined age-dependent molecular, cellular and functional striatal attributes in SCA1 (f-ATXN1146Q/2Q) knockin mice, by assessing RNA-sequencing, immunohistochemistry and electrophysiology. Striatal mRNAs are downregulated in SCA1 mice, many in common with HD mice, and specificity in MSNs is supported by the rescue of transcriptomic dysregulation with deletion of mutant Ataxin1 from MSNs. Immunohistochemistry assessed dopamine receptor 1 (D1R) and 2 (D2R) expression in indirect and direct MSNs. In HD mice (HttQ175/Q7), expression of both D1R and D2R proteins in MSNs decreased with age in parallel with their RNA levels. In the SCA1 mouse striatum, D1R protein expression decreased with age as seen in murine HD striatum. In contrast, while D2R protein level was decreased similar to D1R protein at 5-weeks of age, by 40-weeks expression of D2R protein recovered to levels recorded in WT mice. Electrophysiological assessment showed a reduction of excitatory synaptic transmission in SCA1 mouse MSNs, indicating functional deficits early in disease. In contrast to cerebellar and many other aspects of SCA1 pathology known to depend on proper nuclear localization of ATXN1 with an expanded polyglutamine, mutating ATXN1s nuclear localization failed to correct striatal MSN RNA and protein downregulations, indicating a difference in how ATXN1 exerts its pathological effects between the cerebellum and the striatum. Together, these data provide a molecular and cellular basis of striatal pathology in SCA1.

neuroscience↗

bioRxiv2025

Multi-modal choroid plexus pathology in aging and Alzheimer's disease

Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimers disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology.

neuroscience↗

bioRxiv2026

Human iPSC-derived CNS and retinal microvasculature-on-a-chip models recapitulate hallmarks of diabetic microvascular pathology

The central nervous system microvasculature (CNS-mv) protects neural tissue from harmful substances while supplying oxygen, nutrients, and signaling molecules. Metabolic diseases such as diabetes induce pathological changes in these microvasculatures, leading to severe outcomes including stroke and diabetic retinopathy. Blood vessels in the brain and retina share similarities and undergo comparable pathological alterations in diabetic patients. However, mechanistic understanding of CNS-mv pathogenesis remains limited due to the lack of physiologically relevant in vitro models. Here, we developed three complementary human iPSC-derived microvascular models: (1) a CNS-mv-on-a-chip for mechanistic studies, (2) scalable 3D microvasculature drops for high-throughput screening, and (3) an inner blood-retinal barrier-on-a-chip incorporating Muller glia. All platforms self-assembled into perfusable networks with high pericyte (PC) coverage and barrier function. We identified the TNF-/NF-{kappa}B pathway as the central mediator of hyperglycemia-induced vascular damage, accompanied by robust induction of inflammatory cytokines IL-1{beta} and IL-6. Importantly, cell-type-specific analysis revealed distinct inflammatory roles: endothelial cells (ECs) predominantly activated TNF-/NF-{kappa}B downstream signaling, whereas pericytes selectively upregulated IL-1{beta}, suggesting a coordinated EC-PC inflammatory crosstalk driving vascular pathology. Functionally, both hyperglycemia and TNF-/IL-1{beta} exposure induced vascular regression, reduced PC coverage, and increased ghost vessel formation, confirming these cytokines as key effectors of diabetic microvascular damage. Uniquely, Muller glia showed divergent behavior from PCs, enhancing their perivascular sheath under inflammation - indicating reactive gliosis rather than protection. Together, these in vitro platforms provide a versatile and physiologically relevant hiPSC-based system for mechanistic studies, screening anti-inflammatory therapeutics and developing glia-targeted interventions.

cell biology↗

bioRxiv2026

Agomelatine drives sex-specific neuroprotection and reduced pathology in rat and human Alzheimer's models

Alzheimers disease (AD) remains without effective disease-modifying therapies, underscoring the need for interventions that target interconnected molecular and cellular processes driving cognitive decline. Leveraging a cross-species translational framework integrating a progressive rat model of Alzheimers disease with human iPSC-derived neurons carrying familial AD mutations, we identify agomelatine (AGO) as a disease-modifying candidate. A clinically used melatonergic agonist and 5-HT2C serotonergic antagonist, we found that AGO acts as a sex-selective modulator of AD-related neuronal and microglial dysfunction with therapeutic relevance across species. TgF344-AD rats and their wildtype littermates received chronic dietary AGO ([~]10 mg/kg/day) from 5 to 11 months of age and underwent hippocampal-dependent spatial learning assessment, quantitative hippocampal histopathology, and bulk RNA sequencing to evaluate the therapeutic effect on cognition, pathology, and molecular mechanisms. Human isogenic iPSC-derived cortical neurons carrying PSEN2N141I or APPV717I mutations were treated with 20 {micro}M AGO followed by bulk RNA sequencing, to define AGO-driven transcriptional pathway modulation in AD neurons In TgF344-AD rats, AGO produced robust female-specific benefits. AGO selectively restored hippocampal-dependant cognitive performance in female but not male transgenic rats. These improvements were independent of amyloid burden and instead aligned with reductions in microgliosis and pathogenic AT8-positive tau phosphorylation. Additionally, AGO normalized reactive and amoeboid microglial states exclusively in females and enhanced doublecortin-defined neurogenesis without altering mature NeuN neuronal density. This coordinated hippocampal stabilization highlights AGOs capacity to restore plasticity rather than simply suppress pathology. Transcriptomic analyses revealed sex-divergent mechanisms underlying these effects. In females, AGO activated metabolic, oxygen-handling, lipid-processing, neuroimmune, and CREB/IGF-1 signaling pathways while suppressing ER-stress, epigenetic, and ion-channel transcripts, changes consistent with resilience-promoting cellular reprogramming. In males, AGO preferentially modulated mitochondrial redox biology, transcriptional regulators, and extracellular matrix components. Despite these differences, both sexes showed AGO-induced engagement of conserved AD-relevant pathways, including shared induction of synaptic plasticity and hemoglobin/oxygen-transport related genes, suggesting a convergent neuroprotective molecular signature. To translate these findings to a human system, we examined AGOs effects in PSEN2N141I and APPV717I iPSC-derived cortical neurons. Both mutations produced convergent deficits in synaptic integrity, neuronal maturity, trophic signaling, proteostasis, metabolism, and excitability, alongside dysregulated developmental and ECM-remodeling programs. AGO partially reversed these pathogenic transcriptional changes, up-regulating synaptic, metabolic, vesicle-trafficking, and redox-stress resilience genes while suppressing pathological developmental and inflammatory pathways, demonstrating conserved engagement of neuronal recovery programs. Together, these results identify AGO as a promising non-amyloid therapeutic candidate capable of modulating AD-relevant pathways in rodents and human models. The sex-selective efficacy observed in vivo, combined with conserved transcriptional responses across species, underscores the translational relevance of AGO-driven molecular reprogramming in AD.

neuroscience↗

bioRxiv2026

The core herpes simplex-1 fusion complex drives cell-to-cell spreading of pathological Tau

Neurodegenerative diseases such as Alzheimers disease (AD) are characterized by the pathological aggregation of the host-encoded protein Tau into amyloid fibrils. Pathologic protein aggregates composed of Tau are able to spread from cell-to-cell, thereby contributing to disease progression. The exact mechanisms of intercellular dissemination remain ill-defined. Mounting evidence links the herpes simplex virus-1 (HSV-1) to the aetiology of AD. HSV-1 is a prevalent neurotropic virus that replicates in epithelial cells at the site of infection, and subsequently establishes lifelong latency in the peripheral and central nervous systems. In the quiescent latent state, AD brains show elevated expression of structural viral proteins in the absence of virus production. We hypothesized that HSV-1 glycoproteins involved in viral attachment and fusion facilitate the intercellular spreading of proteopathic seeds. Using cellular models, we demonstrate that expression of the HSV-1 core fusion complex, essential for viral entry and direct cell-to-cell transmission, is sufficient to promote aggregate dissemination between cells. Moreover, anti-HSV-1 antibodies present in the cerebrospinal fluid of patients with HSV-1 encephalitis efficiently neutralize viral infection, block viral cell-to-cell transmission, and inhibit propagation of pathological Tau. Thus, latent HSV-1 infection of the brain could contribute to neurodegenerative disease progression, and antiviral antibodies may represent a potential therapeutic strategy.

neuroscience↗

bioRxiv2026

Spatially resolved transcriptome-metabolome integration reveals region-specific glial lipid dysregulation associated with Alzheimer's pathology

Glial cells maintain the brains lipid and energy balance, and their breakdown is increasingly recognized as a causal contributor to Alzheimers disease (AD). While this concept is established, no approach has directly shown how glial homeostatic failure manifests across brain regions and microenvironments or how it links local pathology, such as plaques, to global metabolic imbalance. To address this gap, we developed iMIST, an integrated platform that combines MALDI-based metabolite imaging, histology, and spatial transcriptomics within a single tissue section to align molecular and anatomical information. Using a mouse model of late-onset AD that recapitulates both amyloid deposition and metabolic vulnerability, iMIST revealed that glial lipid dysregulation is widespread but spatially specialized. In gray matter, plaque-associated microglia were associated with upregulated glycerophospholipid-remodeling in cortico-thalamic areas indicating metabolic stress around local pathology. In contrast, white matter tracts rich in lipid-producing oligodendrocytes show plaque-independent deficits in galactosylceramide metabolism reflecting their high myelin demand. Both processes intensify with age, transforming adaptive glial responses into persistent metabolic dysfunction. Together, these findings demonstrate the spatial interplay between global glial metabolic imbalance and local microenvironmental stressors associated with AD pathology. By integrating transcriptomic and metabolomic information in situ, iMIST provides a framework for uncovering how regional glial vulnerability shapes the pathogenesis of neurodegenerative diseases.

neuroscience↗

bioRxiv2026

D-Methionine Improves Spatial Navigation and Attenuates Oxidative Stress and Amyloid Pathology in a Sex-Specific Manner

BackgroundOxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimers disease (AD) and represent therapeutic targets beyond amyloid-centered approaches. ObjectiveTo determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD mouse models. MethodsMale and female APP/PS1 and APPNL-F mice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic and inflammatory markers, and hippocampal microglial phenotypes were evaluated using biochemical and histological analyses. ResultsD-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APPNL-F mice. APPNL-F males exhibited improved learning during Morris water maze (MWM) acquisition. Amyloid pathology was modestly and region-specifically reduced, including decreased hippocampal plaque size in male APPNL-F mice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-{beta} (A{beta})42 in male APP/PS1 mice. Lipid peroxidation, assessed by malondialdehyde, was reduced only in female APPNL-F mice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue (pgWAT) IL-6 expression in female APPNL-F mice. In the hippocampus, D-Met remodeled microglial signatures, with female APPNL-F mice showing reduced Iba1 and disease-associated microglial (DAM) markers and increased Axl expression. ConclusionShort-term D-Met acts as a metabolic and redox modulator with modest amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APPNL-F mice.

neuroscience↗

bioRxiv2026

Integrating UHPLC-MS and MALDI-MSI for Spatial Nucleoside Profiling in FFPE Breast Cancer: A Multimodal Molecular Pathology Framework

Formalin-fixed, paraffin-embedded (FFPE) tissues constitute the primary material for diagnostic pathology and retrospective clinical research, yet their use in metabolomics remains limited due to molecular cross-linking and analyte degradation. Here, we establish a cost-efficient molecular pathology workflow that integrates ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to quantify and spatially map nucleosides in FFPE breast cancer tissues. Optimized extraction using methanol yielded nucleoside profiles comparable to fresh-frozen tissues, while MALDI-MSI enabled the spatial visualization of nine nucleosides across distinct histological regions. Several nucleosides including deoxyadenosine and 5-formylcytosine showed strong discriminatory power between tumor stages, revealing progressive metabolic rewiring during breast cancer progression. Finally, spatial nucleoside patterns observed in a murine model were recapitulated in patient-derived FFPE tissues, underscoring the translational potential of nucleoside-based spatial metabolomics for clinical research and biomarker discovery. Together, this workflow establishes MALDI-MSI as a powerful and scalable spatial molecular pathology tool for interrogating nucleoside biology in archival breast cancer samples. Following MALDI-MSI, the same FFPE tissue sections can undergo laser capture microdissection, enabling genomic, proteomic, or targeted metabolomic profiling of MSI-defined tumor niches and microenvironmental regions. This integration directly links spatial nucleoside signatures to molecular alterations relevant to precision oncology in future.

cancer biology↗

bioRxiv2026

Intrathecal (G4C2)149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks

A repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G4C2)149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, glial activation, and sparse phosphorylated TDP-43 pathology. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.

neuroscience↗

bioRxiv2026

A Degron Decoy System Co-opts Pathological Seeding to Enable Clearance of Multimeric α-Synuclein.

Pathological seeding of protein misfolding is a hallmark of proteinopathies. However therapeutic strategies to clear these aggregates are lacking, impairing both study of their biological importance in disease etiology and progression as well as development of therapeutics. This is due in part to the need to selectively clear oligomerized proteins whilst leaving functional monomers intact, as well as the challenge of developing molecules that act on the full complement of misfolds the protein can adopt throughout the course of disease. In this work, we describe a dopant system consisting of an engineered alpha-synuclein protein construct that rapidly co-aggregates into existing WT alpha-synuclein oligomers, enabling rapid degradation of the entire assembly in the presence of a small molecule trigger. This work provides proof-of-principle for an approach that transforms pathological seeding from a disease-driver into a therapeutic vulnerability, and is potentially applicable to any proteinopathy without requiring a small molecule binder of the pathologic species.

pharmacology and toxicology↗

bioRxiv2026

CXCL10 drives female-specific tau pathology progression and defines sex-dependent vulnerability in tauopathy model mice

Neuroinflammation is a central driver of tauopathy, yet the precise chemokines that orchestrate the inflammatory microenvironment remain elusive. Here, we report C-X-C motif chemokine ligand 10 (CXCL10) is markedly upregulated in the brains of tauopathy model mice, where it co-localizes with prominent tau pathology. Notably, genetic ablation of Cxcl10 in these mice significantly attenuates tau burden and extends the survival period, specifically in a female-dependent manner. Mechanistically, although Cxcl10 deficiency reduces the number of brain T cells in both sexes, this reduction does not correlate with the female-specific rescue of the phenotype. Furthermore, Cxcl10 deficiency did not alter glial cell activation or motor function, suggesting a sex-specific mechanism. We show CXCL10 is primarily produced by pathological glia, fostering a localized inflammatory microenvironment. Our findings identify CXCL10 as a key mediator of tau pathology and reveal a sex-dimorphic regulatory axis that operates independently of T cell and glial activation paradigms.

neuroscience↗

bioRxiv2026

Fine-scale behavioural dynamics separates adaptive sickness behaviour from injury and infection pathology

Animals commonly reduce activity during infection, but it remains unclear when such "sickness behaviours" reflect adaptive host regulation versus injury responses or pathogen-driven pathology. We combined high-resolution behavioural phenotyping with experimental partitioning of injury, immune stimulation, and live bacterial infection to dissect these effects in Drosophila melanogaster. Using an outbred fly population, we tracked individual locomotor activity at 1 minute resolution for 400 hours in males and females subjected to one of four treatments: unhandled control, septic injury with buffer, immune stimulation with heat killed Pseudomonas entomophila, or septic infection with live P. entomophila. Across the early post-challenge window, total activity diverged most strongly between the unhandled control and the challenged treatments. Fine-scale analyses revealed that immune challenge primarily reshaped the microstructure of movement: the number of activity bouts changed little, whereas active bout lengths were shorter and inactive periods were modestly prolonged, especially in females. Among infected flies, individuals that died early exhibited a collapse of bout structure, showing prolonged inactivity punctuated by brief, sometimes intense, movements, whereas longer-lived infected flies maintained patterns closer to controls. These behavioural differences were detectable in the very early stages of infection: within the first 24-hours post-infection early-dying flies had both a reduced probability of initiating movement from rest and a reduced probability of sustaining on-going activity, consistent with pathogen-induced debilitation; longer-lived infected flies showed near-normal state-transition profiles. This early suppression of activity in acutely dying males was positively associated with subsequent survival time, suggesting a contribution of adaptive restraint alongside pathology. By resolving fine-scale behaviour and state-transition dynamics, our approach clarifies which aspects of "sickness behaviour" are likely adaptive and which signal pathology.

animal behavior and cognition↗

bioRxiv2026

Expansion Revealing of Pathology Resolves Nanostructures Associated with Inflammatory Phenotypes in COVID-19 Decedent Human Brain Tissue

Expansion revealing (ExR) elucidates cellular organization by separating proteins within dense nanostructures by 20x linear expansion, but requires fixation procedures incompatible with human pathology specimens. Here, we report ExR of pathology (ExRPath), which attains [~]20 nm resolution and decrowding of such tissues, through iterative 20x expansion, adapted to human brain pathology specimens. We also report a single-shot 15x expansion protocol for such tissues (15ExMPath), achieved through one-shot 15x expansion. Applying ExRPath and 15ExMPath to COVID-19-decedent brain tissue reveals periodic amyloid nanoclusters that co-localize with SARS-CoV-2 in a rare minority of patient specimens, pointing to a potential neuroinflammatory phenotype associated with COVID-19, and highlighting the power of high-throughput nanoimaging, empowered by expansion microscopy, for discovering potential novel disease mechanisms.

neuroscience↗

bioRxiv2026

Microbiome Integrity Protects Against Glial-Mediated Tau and Amyloid Pathology Through Circadian and Autophagy Homeostasis

Alzheimers disease (AD) is characterized not only by tau and amyloid-{beta} aggregation but also by systemic disruptions in circadian rhythms, metabolism, and gut-brain communication that exacerbate neuroinflammation and neurodegeneration. While glial cells play central roles in inflammatory signaling and proteostasis, the contribution of the gut microbiome to glia-driven AD pathology remains poorly understood. Here, we used Drosophila models with glial-specific expressions of human tau and amyloid-associated transgenes to investigate how microbiome integrity influences disease progression. AD models exhibited significant shifts in gut microbial composition, particularly in Lactobacillus and Acetobacter species, suggesting an adaptive microbial response to pathological stress. Strikingly, microbiome depletion (axenic condition) markedly worsened behavioral and physiological outcomes, including disrupted sleep-circadian rhythms, impaired memory, and reduced locomotor function. These deficits were accompanied by amplified neuroinflammatory signaling (Upd-Dome-Hop-Stat92e axis), increased apoptotic gene expression, lipid dysregulation, and altered synaptic markers. Moreover, microbiome loss induced energy stress marked by elevated phospho-AMPK (p-AMPK), yet failed to restore proteostasis, as evidenced by accumulation of ubiquitinated proteins and the autophagy adaptor Ref2p, indicating impaired autophagic flux. This dysfunction correlated with increased tau, phospho-tau, and A{beta}42 accumulation. Together, our findings demonstrate that microbiome depletion exacerbates glial-mediated inflammation, disrupts circadian and metabolic homeostasis, impairs, and accelerates cognitive and motor decline. This work highlights a previously underappreciated role of the gut microbiome in restraining glial dysfunction and mitigating AD-like pathology, positioning microbial homeostasis as a critical modulator of neurodegenerative disease progression.

neuroscience↗

bioRxiv2026

Gut bacterial Infection drives Parkinsonian pathology in LRRK2 G2019S Knock-in Mice

The LRRK2 G2019S mutation is one of the most common genetic risk factors for Parkinsons disease (PD), yet LRRK2 G2019S knock-in (KI) mice rarely develop robust neurodegeneration under basal conditions, suggesting that additional environmental triggers are required for disease progression. Here, we established a clinically relevant gene-environment interaction mouse model of PD by subjecting LRRK2 G2019S KI mice to recurrent Citrobacter (C.) rodentium infection, a murine model of enteric bacterial inflammation. Repeated infection induced progressive PD-like phenotypes selectively in KI mice, including motor impairment, reduced locomotor activity, impaired motor coordination, selective nigrostriatal dopaminergic neurodegeneration, enhanced neuroinflammation, and pathological phosphorylated -synuclein (p-Syn) accumulation, whereas wild-type (WT) mice remained largely resistant. Mechanistically, infected KI mice developed markedly exacerbated colonic inflammation, epithelial barrier dysfunction, increased intestinal permeability, and enhanced inflammasome activation despite normal bacterial clearance, indicating that pathogenic LRRK2 signaling amplifies inflammatory responses rather than impairing antimicrobial defense. In parallel, recurrent infection induced pronounced intestinal p-Syn accumulation and expansion of pathology beyond the epithelial layer in KI mice, supporting a gut-brain axis mechanism linking intestinal inflammation to neurodegeneration. Collectively, these findings demonstrate that the LRRK2 G2019S mutation functions as a sensitizing factor that cooperates with recurrent enteric inflammation to drive PD- related pathology. This study establishes a physiologically relevant LRRK2 G2019S gene- environment interaction mouse model that recapitulates key behavioral, neuropathological, and inflammatory features of PD.

immunology↗

bioRxiv2026

α-Synuclein pathology differentially alters T-type calcium currents in vulnerable and resilient substantia nigra dopaminergic subpopulations.

Aggregation of -synuclein protein is a characteristic of Parkinsons disease pathology that relates to the degeneration of vulnerable dopaminergic neurons and motor symptoms of the disease. However, -synuclein pathology can contribute to neuronal dysfunction by disrupting several processes within the cell, including intracellular calcium balance, mitochondrial function, and synaptic function. Here, we use a preformed fibril (PFF) model of synucleinopathy to examine effects of striatal -synuclein seeding on dopamine neurons of the substantia nigra pars compacta (SNc). The SNc is heterogeneous and contains dopaminergic neurons with differential vulnerability to Parkinsons disease pathology. We found that intrastriatal injections of PFFs differentially affect these SNc neuron subtypes by increasing the excitability of resilient SNc neurons, while altering tonic firing patterns and T-type calcium currents in vulnerable SNc neurons. In addition, we performed comprehensive electrophysiological analyses and neural morphology reconstructions on SNc neurons from PFF and monomer injected mice. These findings provide insights to the selective vulnerability of SNc neuron subtypes and further our understanding of the role of -synuclein in Parkinsons disease progression and circuit dysfunction.

neuroscience↗

bioRxiv2026

ZDHHC14-Mediated Palmitoylation of TBK1 Promotes Pathological Cardiac Hypertrophy via Type I Interferon Signaling Activation

Pathological cardiac hypertrophy represents a common maladaptive response to cardiovascular stress and constitutes a major harbinger of heart failure. Although S-palmitoylation--a reversible post-translational modification--critically governs protein localization, trafficking, and stability, its involvement in cardiac hypertrophy remains poorly characterized. In this study, we aimed to explore the role and regulatory mechanism of a palmitoyltransferase, zinc finger DHHC-type palmitoyltransferase 14 (ZDHHC14), in cardiac hypertrophy. We found that ZDHHC14 was significantly upregulated in cardiac hypertrophy tissues from both human patients and mouse models. Cardiomyocyte-specific ZDHHC14 knockdown ameliorated transverse aortic constriction (TAC)-induced cardiac hypertrophy and dysfunction in male mice, whereas cardiac-specific ZDHHC14 overexpression via AAV9 exacerbated these pathological phenotypes. Mechanistically, TANK-binding kinase 1 (TBK1) was identified as a novel substrate of ZDHHC14 through interactomic screening. ZDHHC14 catalyzed TBK1 palmitoylation at cysteine 267, which in turn facilitated TBK1 phosphorylation and subsequent activation of type I interferon (IFN-I) signaling, ultimately promoting cardiac hypertrophy. Importantly, our findings demonstrate that the TBK1-C267S mutation rectifies ZDHHC14 overexpression-induced exacerbation of cardiac hypertrophy. This study illustrated a ZDHHC14-TBK1-IFN-I axis in regulating cardiac hypertrophy, which may provide a potential therapeutic target to ameliorate pathological cardiac hypertrophy.

molecular biology↗

bioRxiv2026

ARID5B drives an inflammatory-to-destructive shift in pathologic fibroblast behavior

During inflammatory diseases such as rheumatoid arthritis, fibroblasts prominently drive chronic inflammation and the subsequent destruction of cartilage and bone. The mechanism by which an activated, inflammatory fibroblast acquires tissue destructive behaviors is unknown. Here, we describe ARID5B as a transcription factor that directs inflammatory fibroblasts to become migratory and invasive. Upon upregulation in inflammatory fibroblasts, ARID5B binds to histone editors and localizes to both inflammatory and invasive gene loci, epigenetically repressing pro-inflammatory genes while enhancing expression of pro-invasive genes. Likewise, fibroblast-specific ARID5B overexpression in vivo drives an inflammatory-to-erosive shift in arthritis pathology. Our findings highlight ARID5B as a maladaptive brake on inflammatory fibroblast activation that endows fibroblasts with pathologic invasive properties, thus mechanistically linking fibroblast-driven tissue inflammation to tissue damage. These insights into the regulation of inflammatory and invasive fibroblast pathology may inform successful therapeutic targeting of fibroblasts in inflammatory diseases.

immunology↗