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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2019

Mapping chromatin accessibility and active regulatory elements reveals new pathological mechanisms in human gliomas

Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We performed whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel novel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we created an atlas of active enhancers and promoters in benign and malignant gliomas. We explored these elements and intersected with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas. SignificanceEpigenetics-driven deregulation of gene expression accompanies cancer development, but its comprehensive characterization in cancer patients is fragmentary. We performed whole-genome profiling of gene expression, open chromatin, histone modifications and DNA-methylation profiles in the same samples from benign and malignant gliomas. Our study provides a first comprehensive atlas of active regulatory elements in gliomas, which allowed identification of the functional enhancers and promoters in patient samples. This comprehensive approach revealed epigenetic patterns influencing gene expression in benign gliomas and a new pathogenic mechanism involving FOXM1-driven network in glioblastomas. This atlas provides a common set of elements for cross-comparisons of existing and new datasets, prompting novel discoveries and better understanding of gliomagenesis. HighlightsO_LIWe provide an atlas of cis-regulatory elements active in human gliomas C_LIO_LIEnhancer-promoter contacts operating in gliomas are revealed C_LIO_LIDiverse enhancer activation is pronounced in malignant gliomas C_LIO_LIChromatin loop activates FOXM1-ANXA2R pathological network in glioblastomas. C_LI

cancer biology↗

bioRxiv2019

Fibroblast growth factor-2 prevents synaptic pathology in minimal hepatic encephalopathy via NRG1/ErbB4 signaling

BackgroundMinimal hepatic encephalopathy (MHE) is implicated in the impairment of memory function. Fibroblast growth factor-2 (FGF2) is involved in modulating synaptic and neuronal formation. MethodsThe aim of this study is to examined the impacts of FGF2 on MHE pathology. Our study addressed whether FGF2 could trigger neuregulin-1 (NRG1) release to ameliorate synaptic impairment in MHE rats and in primary cultured neurons. ResultsThe results showed the decreased FGF2 expression in MHE brains. After treatment with FGF2, secreted neuregulin-1 (NRG1) and ErbB4 were increased, and the interaction of the 2 proteins was enhanced. Additionally, treatment with FGF2 or NRG1 induced synaptic formation, with increase in the activity of synapse and the density of dendritic spine, through Sirt1. NRG1 signaling was prevented by administration of FGF2, which acts through the FGFR1 in MHE rats. Finally, intracerebroventricular injection with FGF2 or NRG1 mitigated the impairment of synaptogenesis. ConclusionThe data suggest that FGF2 may be a promising latent therapeutic reagent for MHE pathogenesis.

neuroscience↗

bioRxiv2025

Stable neuronal representations to repeated stimulation underlie cognitive resilience in Alzheimer's disease pathology

While Alzheimers Disease (AD) typically triggers cognitive decline, some individuals with significant AD pathology maintain normal cognition into late life. Understanding the neuronal underpinnings of such cognitive resilience would propel the development of interventions for delaying dementia. To this end, we used cognitive testing to identify a subset of cognitively resilient 13-month-old TgF344-AD rats (established AD) and their non-transgenic littermates, followed by Neuropixels recording from 8500 neurons during repeated somatosensory stimulation. Cognitively resilient TgF344-AD rats recruited fewer neurons yet displayed more stable neuronal representations during repeated stimulations in cortical excitatory and hippocampal inhibitory ensembles, with reduced excitatory spike burstiness during network activation and a distinct pattern of functional synaptic connectivity. These associations existed independently of amyloid and tau levels. For the first time, our study revealed neuronal population-level hallmarks of maintained cognition that may serve as a novel neurophysiological biomarker of cognitive resilience and a target for stabilizing cognition.

neuroscience↗

bioRxiv2025

Spatiotemporal remodeling of chromatin topology architecture and H3K27me3 redistribution underlies vascular pathology in Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disorder driven by the accumulation of the lamin A variant, progerin, leading to severe vascular pathology. While epigenetic alterations are implicated, the spatiotemporal reorganization of the higher-order chromatin and its functional impact on vascular smooth muscle cell (VSMC) transcription remain poorly defined. Through an integrated, longitudinal multi-omics approach combining in situ high-throughput chromosome conformation capture (Hi-C) and Cleavage Under Targets and Tagmentation (CUT&Tag) profiling of CTCF, SMC1A, H3K27me3, H3K27ac, and H3K36me3 with transcriptomic analyses from control and HGPS iPSC-derived VSMCs, we reveal that global topologically associating domain (TAD) architecture remains largely intact in HGPS. However, the internal chromatin states of TADs undergo dynamic, passage-specific remodeling, characterized by a progressive accumulation of broad H3K27me3-repressed domains. This is accompanied by a loss of A/B compartment segregation, as confirmed by DNA-FISH, and a pronounced depletion of interchromosomal intermingling, specifically surrounding downregulated genes, suggesting that these interchromosomal contacts are essential for maintaining transcriptional competence in normal VSMCs. Crucially, we uncover widespread rewiring of enhancer-promoter (E-P) loops, which is linked to the dysregulation of genes critical for vascular development, extracellular matrix organization, and atherosclerosis. Our study demonstrates that spatiotemporal redistribution of repressive histone marks and reorganization of E-P interactions within a structurally resilient TAD framework underpin widespread transcriptional dysregulation in HGPS vascular pathogenesis. This uncovers a critical dissociation between higher-order chromatin architecture and histone modification landscape, providing a mechanistic basis for the failure of vascular homeostasis in progeria.

genomics↗

bioRxiv2025

Aberrant medial entorhinal cortex dynamics link tau pathology to spatial memory impairment

Tau pathology in the entorhinal cortex (EC) is associated with spatial memory decline in aging and early-stage Alzheimers disease, but its impact on EC computations during learning is not well understood. We performed longitudinal two-photon calcium imaging of layer 2 excitatory neurons in the medial EC (MEC) of PS19 tauopathy mice over 10 days of an operant spatial learning task. Male PS19 mice showed marked learning impairments accompanied by dysregulated MEC activity and unstable spatial coding. Their activity also showed weakened representations in cue-poor relative to cue-rich regions, correlated with attenuated speed modulation. These changes suggest that impaired path integration destabilizes MEC spatial maps, leading to impaired spatial memory. In contrast, female PS19 mice exhibited only mild behavioral and neural deficits despite a comparable tau burden, suggesting sex-specific resilience. Among MEC cell types, pyramidal cells accumulated more phosphorylated tau than stellate cells and displayed the most severe functional disruption, linking cellular tau load to circuit dysfunction. Finally, general linear models of MEC activity reliably predicted learning performance, highlighted particularly strong contributions from non-grid and pyramidal cells, and accurately classified PS19 versus wild-type mice. These findings identify aberrant MEC dynamics as a key circuit mechanism underlying tau-related spatial memory deficits and point to early diagnostic and circuit-targeted therapeutic strategies.

neuroscience↗

bioRxiv2026

Interorganelle competition for linoleic acid underlies steatotic liver pathology

Lipid droplets (LDs) are traditionally viewed as protective organelles that sequester potentially cytotoxic lipids. However, whether and how LD biogenesis in pathological contexts actively rewires interorganelle lipid homeostasis to drive organelle dysfunction and disease progression remains unexplored. Here, we identify the adipocyte-enriched protein calsyntenin 3{beta} (CLSTN3B) as a critical promoter of metabolic dysfunction-associated steatotic liver disease (MASLD). CLSTN3B, an ER-LD contact protein previously shown to support LD maturation in adipocytes, is robustly induced in mouse hepatocytes by peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) in response to dietary caloric overload. CLSTN3B drives LD biogenesis and neutral lipid storage by stabilizing hemifusion-like ER-LD membrane bridges via its arginine-rich segment. These bridges preferentially recruit cone-shaped linoleoylated phosphatidic acid (PA), diverting linoleic acid (LA) into triacylglycerides (TAGs) rather than mitochondrial cardiolipin (CL), leading to disrupted cristae architecture, deficient ETC supercomplex assembly, elevated electron leak, and oxidative stress. Hepatocyte-specific CLSTN3B deletion impairs LD formation, reduces TAG accumulation, enhances fatty acid oxidation, restores CL maturation, and mitigates oxidative stress, collectively attenuating MASLD progression. Consistently, hepatic CLSTN3B expression correlates with fibrosis severity and progression in human MASLD. These findings position LDs as active regulators of interorganelle lipid partitioning and establish CLSTN3B as a key determinant of mitochondrial vulnerability, providing a general framework for how dysregulated organelle interfaces shape disease.

cell biology↗

bioRxiv2026

Osteoprotegerin-Enabled Immune Evasion by Pathological Adipose Stromal Cells Drives Metabolic Dysfunction in Obesity

Diet-induced obesity (DIO) promotes the accumulation of stromal cells with senescent characteristics in the adipose tissue (AT). Selectively clearing these cells--either through chemical senolytics or activation of invariant natural killer T (iNKT) cells--improves glucose homeostasis in obese mice, however the identity of the responsible stromal population remains unknown. Here, we use transcriptional profiling of AT stromal cells coupled with C12FDG-based enrichment of senescent populations in mice with DIO and healthy controls to identify a distinct subset of adipose progenitor cells (APCs) with robust senescence signatures that accumulate in DIO across multiple AT depots. We show that these cells, which we term senescent APCs (sAPCs), are not merely passive markers of metabolic stress but are instead active stromal organizers, accumulating in parallel with the emergence of lipid-associated macrophages (LAMs) and the diminution of multipotent mesenchymal progenitors. sAPCs promoted CCR2-dependent macrophage chemotaxis, directly linking stromal senescence to chemokine-mediated remodeling of the AT immune niche. Comparative transcriptional analysis revealed a remarkable similarity between sAPCs and inflammatory cancer-associated fibroblasts (iCAFs), including the strong induction of periostin (POSTN) and the production of osteoprotegerin (OPG), a decoy receptor for RANKL and TRAIL that enables tumoral immune evasion. Indeed, OPG production by AT stromal cells was induced by DIO across AT depots. Exogenous OPG inhibited the ability of iNKT cells to kill senescent APCs in vitro, whereas antibody-mediated OPG neutralization reciprocally enhanced such cytotoxic killing. In vivo, systemic OPG neutralization both reduced sAPC accumulation in AT and normalized glucose homeostasis in obese mice. Together, these findings identify sAPCs as a pathological stromal population that expands in obesity through elaboration of immunomodulatory factors. In particular, secreted OPG enables sAPCs to evade iNKT-mediated immune surveillance and contributes to metabolic dysfunction, highlighting OPG and sAPCs as promising therapeutic targets for restoring AT immune and metabolic homeostasis.

immunology↗

bioRxiv2026

Addressing diagnostic gaps in thyroid pathology: a multiplex protein panel as an adjunctive tool for risk stratification and differentiation of thyroid neoplasms

Fine-needle aspiration biopsy of thyroid nodules frequently yields indeterminate results, leading to unnecessary diagnostic surgeries. We evaluated a targeted plasma proteomics approach to differentiate benign follicular thyroid adenoma (FTA) from malignant papillary thyroid carcinoma (PTC). Using LC-MRM mass spectrometry with stable isotope-labeled standards (SIS), we quantified a multiplex protein panel in plasma samples from 267 patients. The analytical workflow incorporated an MS-based assessment of preanalytical hemolysis to prevent bias associated with thyroid-related blood composition changes and multiple rounds of randomization allowed assessment of batch effects. While previously proposed low-abundance thyroid cancer markers were rarely detected in the cohort, a signature of high-abundance plasma proteins successfully stratified the patients. The malignant PTC phenotype was characterized by a significant increase in apolipoprotein A1 and myosin-9, along with elevated CD14 and kininogen-1. Benign FTA was associated with higher levels of acute-phase proteins, including ceruloplasmin and complement C1q subunit C. Simple PCRE model with 20 parameters based on 4 major plasma proteins allowed to build a classifier with specificity that can be adjusted with regard to epidemiology and medical resource. This study establishes a foundational mass spectrometry-based framework that utilizes systemic proteomic profiles to differentiate underlying pathologies and improve clinical decision-making regarding patient management. By enabling additional stratification of patients with Bethesda IV cytology, who are otherwise frequently subjected to unwarranted diagnostic operations, this multiplex MS approach provides a potential non-invasive triage tool to reduce unnecessary surgical interventions for indeterminate thyroid nodules.

systems biology↗

bioRxiv2026

Neuronal microscale biophysical instability mediates macroscale network dynamics shaping pathological manifestations

Subtle changes in membrane excitability may contribute to neurological disease, but disease-relevant dynamical signatures that generalize across models remain poorly defined. Here, we quantified variability in action potential initiation in Drosophila neurons expressing tauopathy- or epilepsy-associated mutations and in human iPSC-derived neurons from patients with Alzheimers disease or epilepsy. Across these models, disease-associated neurons exhibited increased instability in spike timing relative to controls. In Drosophila neurons, this phenotype was accompanied by increased variability in voltage-gated sodium currents during non-stationary inactivation, identifying a candidate biophysical contributor to altered spike initiation. Antiepileptic drugs reduced sodium-current variability and stabilized spike initiation in fly neurons, and similarly improved spike-timing instability in patient-derived human neurons. In the fly models, neuronal instability was also associated with altered circuit- and brain-state readouts. Together, these findings identify unstable spike initiation as a conserved electrophysiological phenotype across distinct neurological disease models and suggest that sodium-channel-dependent variability may contribute to this phenotype. Rather than establishing a complete multiscale causal framework, our study defines a tractable cellular and dynamical entry point for investigating how subtle perturbations in intrinsic excitability may scale toward circuit dysfunction and disease-relevant phenotypes. Significance StatementLinking microscale neuronal changes to macroscale disease phenotypes remains a key challenge in neuroscience biophysics. Here, we show that neurons from Drosophila models of tauopathy and epilepsy and human iPSC-derived neurons from patients with Alzheimers disease and epilepsy share increased biophysical instability in their local neural activities. In fly neurons, this phenotype is associated with increased variability in voltage-gated sodium currents and is reduced by antiepileptic treatment. These findings define unstable local spike variability as a conserved dynamical signature across distinct disease models and nominate sodium-current variability as a mechanistically testable, pharmacologically reversible contributor to pathological excitability.

neuroscience↗

bioRxiv2026

Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction

The assembly of TAR DNA-binding protein 43 (TDP-43) into amyloid filaments within neurons is a hallmark of multiple neurodegenerative diseases, including motor neuron diseases (MND), frontotemporal dementias (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). These diseases result from the deterioration and loss of neurons, with synaptic dysfunction and neuronal hyperexcitability being prominent early events. Pathogenic mutations in the TDP-43 gene, TARDBP, that promote filament formation have established a causal role for TDP-43 assembly in neurodegenerative diseases. However, the molecular mechanisms underlying filament accumulation and their contribution to neurodegeneration are poorly understood. TDP-43 filaments can propagate between neurons in a prion-like manner, which may underlie the progressive spread and accumulation of TDP-43 pathology in disease. Here, we studied early stages of TDP-43 filament accumulation following internalisation of patient-derived TDP-43 filaments by mouse and human cortical neurons. Using proximity labelling, we identified molecular environments and putative interactions of TDP-43 filaments. We found that TDP-43 filaments accumulated at synapses, particularly in proximity to the presynaptic active zone, which we confirmed in FTD patient brain sections. Electron cryo-tomography (cryo-ET) directly visualised abundant TDP-43 filaments spanning the presynaptic cytoplasm in situ, which contacted synaptic vesicles and the plasma membrane. Functional measurements revealed that the accumulation of TDP-43 filaments led to presynaptic dysfunction and subsequent neuronal hyperexcitability. These findings suggest that synapses are a major early site of TDP-43 filament accumulation, relevant to their propagation, and directly link TDP-43 filament gain of function to synaptic dysfunction.

neuroscience↗

bioRxiv2026

DDX3X syndrome mutations lock DDX3X-RNA conformational states to drive persistent pathological condensation and neuronal death

DDX3X is a highly conserved RNA helicase associated with RNA metabolism, translation initiation, and deciding cell fate choices. Spontaneous mutations in DDX3X cause a rare genetic human disorder called DDX3X syndrome, showing a spectrum of neurodevelopmental and intellectual abnormalities. How missense mutations in DDX3X lead to aberrant cellular functions and pathological consequences is unclear. Here, we demonstrate that specific DDX3X syndrome missense mutations induce the formation of persistent, solid-like DDX3X stress granules by structurally altering the conformation of the DDX3X-RNA complex. Structural interrogation of DDX3X syndrome missense mutations revealed critical mutations that perturb the DDX3X-RNA complex, exhibit high clinical pathogenicity scores, and are associated with cancers. N and C-terminal mutations adjacent to the helicase domain of the DDX3X (F182V, I190S, T198P, L556S, and L559H) showed augmented stress granule (SG) assembly, and formation of persistent DDX3X-SGs in neuronal and non-neuronal cells. Intriguingly, these mutations altered the liquid-like properties of DDX3X-SGs, forming solid-like SGs. Mechanistically, these mutations drive the persistent DDX3X-SGs by either locking DDX3X in an open, RNA-bound conformation or by increasing the rigidity of the DDX3X-RNA complex (I190S; T198P), thereby conferring a loss of liquid-like properties. The persistent solid-like DDX3X-SGs preferentially promoted neuronal lytic cell death and did not affect translation. Also, the C-terminal L556S and L559H mutations, which form persistent granules, promoted the DDX3X-driven {beta}-amyloid aggregation. Our observations indicate that DDX3X syndrome mutations near the N- and C-termini promote the formation of solid-like DDX3X condensates, neuropathological aggregation, and neuronal cell death, which might underlie the disease pathogenesis in humans. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/702492v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@164b436org.highwire.dtl.DTLVardef@73741aorg.highwire.dtl.DTLVardef@1cb6fcforg.highwire.dtl.DTLVardef@119b652_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Chronic Unpredictable Stress Drives Non-pathological, Adaptive Metabolic Hormone Reprogramming with Reduced Insulin Resistance Linked to Depressive-like Behaviors

Major Depressive Disorder (MDD) is increasingly conceptualized as a neuroimmune-metabolic-oxidative stress (NIMETOX) condition, partly driven by environmental stressors. While new antidepressant strategies have emerged to target NIMETOX pathways, the mechanism by which chronic stress reshapes metabolic regulation-particularly in the absence of clinically overt metabolic disease-remain poorly understood. Using a 6-week chronic unpredictable mild stress (CUMS) paradigm in metabolically healthy male and female mice, we evaluated depressive-like behaviors alongside circulating glucose and metabolic hormones, including insulin, resistin, Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon-like Peptide-1 (GLP-1), glucagon, ghrelin, leptin, and Plasminogen Activator Inhibitor-1 (PAI-1). We further assessed whether simvastatin, curcumin, S-adenosyl methionine (SAMe), or pyrrolidine dithiocarbamate (PDTC), an NF-{kappa}B inhibitor, normalize CUMS-induced metabolic and behavioral alterations, using fluoxetine as a reference antidepressant. CUMS induced a hypoinsulinemic state accompanied by enhanced basal insulin sensitivity and reduced insulin resistance, while central appetite regulation and adipose inflammatory profiles remained preserved. Indices of lower insulin resistance were strongly associated with sucrose preference and immobility time. Glucagon and PAI-1 showed positive associations with novel object recognition performance, whereas GIP and leptin were inversely related to open-field activity. Glucose levels correlated positively with rearing behavior. Despite significant improvements in depressive-like behaviors, none of the pharmacological interventions normalized the stress-induced metabolic hormone profile. Marked sex differences were observed, with females displaying a catabolic, immune-ready phenotype and males showing a relative anabolic bias. These findings indicate that CUMS induces a non-pathological, adaptive metabolic hormone reprogramming rather than metabolic dysfunction, supporting the interpretation of stress-related metabolic changes as resilient adaptations within the NIMETOX framework.

neuroscience↗

bioRxiv2026

Modeling the pathological brain-gut axis in Parkinson's disease using human iPSC derived brain-intestinal assembloids

Parkinson disease is increasingly recognized as a systemic disorder involving pathological communication along the brain-gut axis, yet the cellular mechanisms underlying inter-organ -synuclein propagation remain poorly defined. Here, we establish a human induced pluripotent stem cell-derived brain-intestinal assembloid that integrates a developmentally specified medullary hindbrain organoid with an enteric neuron-enriched intestinal organoid. Using this model, we show the propagation of -synuclein from brainstem neurons to enteric neurons. Ligand-receptor analysis combined with genetic perturbation identifies NRXN1-NLGN2 signaling as a key mediator of brain-to-gut -synuclein propagation, with NRXN1 being upregulated in Parkinsons disease patient datasets in vivo. Together, these findings establish a human stem cell-based platform for investigating brain-gut communication and uncover molecular mechanisms underlying -synuclein propagation in Parkinsons disease.

neuroscience↗

bioRxiv2026

Body size, dental pathology and maternal genetic diversity of ancient horses in the eastern Baltic Sea region and western Russia

The early evolutionary history of modern domestic horses (Equus caballus/E. ferus caballus), known as the DOM2 lineage, is well documented due to numerous archaeological and ancient DNA (aDNA) studies. Although many uncertainties remain in the domestication timeline, current evidence suggests that the domestication of modern horses began in the Pontic-Caspian steppe at least [~]2700 BCE (before common era), or even earlier. However, it is not known how long remnant wild horse populations survived or when domestic horses were introduced into Northern Europe. In this study, we review the current knowledge of horse domestication, focusing on Northern Europe. We analysed prehistoric horses from western Russia to assess the body sizes of wild horses from the Ivanovskaya site (5900-3800 BCE) in the Pontic-Caspian steppe, and the body weight of one Lithuanian wild horse (4000-3800 BCE). Additionally, we analysed body sizes of Late Bronze Age-Early Roman Age horses (1100 BCE-300 CE; common era) and re-analysed body sizes and estimated rider weights of historic domestic horses from Lithuania (100-1400 CE). We searched for pathological changes and signs of bit wear indicative of bridling. Furthermore, we investigated maternal genetic diversity by sequencing ancient mitochondrial DNA. We found that wild horses from Ivanovskaya were intermediate in body size between earlier and more recent horses of the Eurasian Steppe, and that the Lithuanian wild horse weighed only [~]270 kg and Late Bronze Age-Early Roman Age horses 200-300 kg. Lithuanian domestic horses were pony-sized (< 130 cm on average). Bit wear was confirmed on one tooth, the oldest domestic horse in Lithuania (799-570 cal BCE). Another tooth showed signs of the Equine Odontoclastic Tooth Resorption and Hypercementosis (EOTRH) condition. Mitochondrial DNA was successfully amplified from one Ivanovskaya wild horse along with 25 other ancient samples, including Lithuanias oldest domestic horse. mtDNA diversity was high, revealing several maternal lineages.

genetics↗

bioRxiv2026

Deep brain stimulation reduces subthalamic nucleus pathological dynamics and rescues gait deficits associated with dopamine loss

The Subthalamic Nucleus (STN) regulates movement and is an important clinical target for deep brain stimulation (DBS) in Parkinsons Disease (PD). However, it remains unclear how dopamine loss and DBS influence STN gait encoding. We performed simultaneous recordings from multiple neurons and intermittent DBS in the STN of healthy and dopamine depleted PD mice during voluntary locomotion. We found that dopamine loss resulted in gait deficits manifested as altered stride length of both hindlimbs and forelimbs, which were rescued by intermittent DBS. Furthermore, dopamine loss exaggerated movement encoding of STN population dynamics, and elevates individual STN spiking during movement and beta-rhythmic firing at rest. Despite an overall increase in the fraction of neuron activated by movement, individual neurons gait encoding properties remain similar between healthy and PD mice. While DBS suppressed firing in both healthy and PD mice, it selectively reduced STN beta-rhythmic spiking, desynchronized STN networks, and rescued gait deficits associated with the loss of dopamine. These results suggest that pathological activation and beta synchronization of the STN contributes to motor deficits related to PD, and DBS-induced reduction of beta rhythmic spiking and STN network desynchronization contribute to the therapeutic effects of DBS in PD.

neuroscience↗

bioRxiv2026

Loss of Lamp2a-dependent chaperone-mediated autophagy drives dry AMD-like retinal pathology in mice and is rescued by BK channel activation

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in elderly individuals for which no effective treatments are currently available. The photoreceptor loss in dry AMD is secondary to the demise of the retinal pigment epithelium (RPE) cells. The accumulation of extracellular deposits, known as drusen, resulting in part from deficient lysosomal and autophagosomal degradation, is a key feature of dry AMD pathogenesis. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains proteostasis by targeting specific cytosolic proteins for lysosomal translocation and degradation. LAMP2A (lysosome-associated membrane protein 2A) functions as the key lysosomal receptor required for CMA. Using Lamp2a knockout mouse, we show that selective CMA dysfunction recapitulates AMD-like pathologies, including sub-RPE lipid and protein deposits, RPE atrophy, Bruchs membrane thickening, and impaired autophagic activity. Furthermore, we identify large-conductance Ca{superscript 2}-activated K (BK) channels as a therapeutic target for restoring autophagic activity. Mechanistically, pharmacological activation of BK channels with the small-molecule agonist GLA-1-1 enhances macroautophagy and stimulates autophagic flux by promoting autophagosome-lysosome fusion. Importantly, oral administration of GLA-1-1 in markedly attenuates structural, functional, and molecular retinal abnormalities in Lamp2a-deficient mice, suggesting that pharmacological activation of macroautophagy through facilitating autophagosome-lysosome fusion can partially compensate for CMA deficiency. Together, these findings demonstrate that pharmacological activation of macroautophagy can ameliorate the retinal phenotype resulting from CMA dysfunction and support BK channel activation by GLA-1-1 as a promising therapeutic strategy for dry AMD.

pharmacology and toxicology↗

bioRxiv2026

Pathological mitochondrial dysfunction mimics an aging pathway in budding yeast

Mitochondrial dysfunction has long been associated with aging and linked to lifespan limitation across many species, including the budding yeast Saccharomyces cerevisiae. However, the widely used S288C laboratory background carries several polymorphisms that impair mitochondrial genome stability and function. Here, using a three-color reporter and single-cell microfluidics, we demonstrate how these mutations cause spontaneous transition to a state with severe mitochondrial deficiency characterized by low membrane potential, loss of heme biosynthesis, activation of iron regulon and morphological changes. Equally affecting young and old cells, this condition-dependent transition creates an apparent split in aging trajectories mimicking an age-dependent pathway. We further identify the mkt1-30D allele as a key genetic modifier of this pathological mitochondrial state. Together, these results suggest that mitochondrial dysfunction in this system reflects a genetic abnormality rather than an intrinsic aging process, calling for a reassessment of its role as a conserved hallmark. Our study also highlights how genetic defects can distort aging progression, potentially obscuring genuine age-associated phenotypes.

cell biology↗

bioRxiv2026

VESTIBULAR FUNCTION LOSS ASSOCIATES WITH SENSORY EPITHELIUM PATHOLOGY IN VESTIBULAR SCHWANNOMA PATIENTS

Vestibular schwannomas (VS) cause vestibular function loss by mechanisms still poorly understood. We evaluated the vestibulo-ocular reflex by the video-assisted Head Impulse Test (vHIT) in patients with planned tumour resection by a trans-labyrinthine approach. The vestibular sensory epithelia were collected and processed by immunofluorescent labelling for confocal microscopy analysis of sensory hair cell subtypes (type I, HCI, and type II, HCII), calyx endings of the pure-calyx afferents, and the calyceal junction normally found between HCI and the calyx (n=23). Comparing Normo-vHIT and Hypo-vHIT patients, we concluded that worse vestibular function associates with decreased HCI and HCII counts in the sensory epithelia and with increased proportion of damaged calyces. A decrease in the number of HCI and calyx endings of the pure-calyx afferents was recorded to associate with age increase. Partial least squares regression (PLSR) models indicated that VS and age had independent, additive effects on vestibular function. Correlation analyses indicated that lower vHIT gains associate with lower numbers of HCI and increased percentages of damaged calyces. These data support the hypothesis that the deleterious effect of VS on vestibular function is mediated, at least in part, by its damaging impact on the vestibular sensory epithelium. They also provide further evidence for the dependency of the vestibulo-ocular reflex on HCI function and for the calyceal junction pathology as a common response of the sensory epithelium to HC stress.

neuroscience↗