Biology subjects

Feng, J.

Publications and source records attributed to Feng, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Successor representation supports structural learning of syllable sequences

Humans efficiently learn the temporal structure of speech, yet the underlying cognitive mechanisms remain unclear. Recent research in visuospatial sequential memory has proposed the successor representation (SR), important in reinforcement learning, which encodes multi-step transitional relationships. To test whether SR also supports the structural learning of rapidly changing speech syllable sequences, we adapted a pyramid-structured sequential learning paradigm using syllable streams presented at a natural speech rate (~ 4 Hz). Participants exhibited robust structural learning, evidenced by asymmetric memory performance modulated by adjacent transitional probabilities. Notably, the SR model captured recognition performance for non-adjacent syllable pairs. Moreover, SR-based learning effects generalized across all syllable sequences, regardless of adjacency. Furthermore, the effectiveness of SR learning was associated with cognitive flexibility and working memory capacity. Together, these findings suggest that humans rely on effortful SR-like mechanisms for the structural learning of syllable sequences, highlighting a modality-general computational principle for sequential learning across various temporal modulation scales.

neuroscience↗

bioRxiv2026

Plasma Proteomic Profiling Identifies a Subset of HIV Elite Controllers with Inflammatory Profiles Resembling People Without HIV

Background: Elite controllers (ECs) are people with HIV (PWH) who suppress viral replication without antiretroviral therapy (ART). A subset, often termed exceptional elite controllers (EECs), harbor very small viral reservoirs, with few intact proviruses integrated into inactive chromosomal regions. Defining inflammatory signatures in ECs may clarify whether some approach a functionally cured state. Methods: We measured 384 plasma proteins in ART-naive ECs (n=62), ART-suppressed non-controllers (n=37), and people without HIV (PwoH) (n=50) using Olink proteomics, and compared proteomic profiles, clinical parameters, and intact reservoir data using FLIP-Seq. Hierarchical clustering identified ECs whose proteomic profiles most closely resembled PWoH; this subset was further analyzed using machine-learning approaches. Results: ART-suppressed non-controllers had higher inflammatory protein levels than ART-naive ECs, yet ECs still showed elevated inflammation and lower CD4:CD8 ratios compared with PWoH. Clustering analysis revealed a distinct subset of ECs (n=9) whose profiles closely matched those without HIV (ECs with PWoH-like proteomic profiles), a pattern not observed in ART-suppressed non-controllers. Compared to typical ECs, ECs with PWoH-like proteomic profiles had consistently lower IL-1{beta}, SCRN1, and BID, numerically lower intact proviral frequencies, and a high frequency of protective HLA alleles. Machine-learning analyses highlighted features that most strongly differentiated ECs with PWoH-like proteomic profiles from typical ECs, including reduced gut mucosal/intestinal epithelial-associated proteins, higher absolute CD4 counts, and lower levels of pro-inflammatory cytokines and cellular immune activation. Conclusions: These findings identify a subset of ECs with a PWoH-like inflammatory proteomic profile, accompanied by numerically lower intact HIV reservoirs and a high frequency of protective HLA alleles. Defining the mechanisms associated with this low-inflammatory state may provide insights into exceptional HIV control and inform strategies for durable HIV remission.

immunology↗

bioRxiv2026

Hippocampal subfields support human novelty detection via distinct signals

Detecting novelty is fundamental to adaptive memory, yet the neural comparisons that allow new events to be distinguished from prior experience are not fully understood. Hippocampal novelty signals are often framed as associative comparator responses that register violations of learned relationships. However, recognition memory models also predict a broader form of comparison: a global, item-based mismatch between an incoming stimulus and aggregate memory traces. Whether such global matching is implemented within human hippocampal circuitry, and whether it contributes to memory decisions, remains unknown. Using ultra-high-field 7T fMRI during dense sampling of a continuous object recognition task (76,800 trials across five sessions), we estimated both univariate novelty responses and multivariate global mismatch signals across hippocampal subfields. CA1 carried the novelty response that most reliably predicted accurate novelty detection, whereas the subiculum expressed a global mismatch signal that predicted detection independently of CA1. This subicular signal also shaped subsequent recognition behaviour, in which low global mismatch was associated with false alarms to novel objects that propagated into later hits. Finally, subicular global mismatch scaled with the experienced similarity of past events, consistent with an item-based comparison against accumulated memory. These findings identify distinct hippocampal mismatch signals for novelty detection and extend the human hippocampal comparator role beyond local associative mismatch to include global, item-based matching.

neuroscience↗

bioRxiv2026

Two dominant axes structure high-dimensional object representations in the human ventral temporal cortex

The ventral temporal cortex is critical for visual object recognition, yet the principles organising its representations remain unclear. Using ultra-high-field 7T fMRI and dense sampling of 1,854 object concepts, we applied exploratory factor analysis to multivoxel response patterns to estimate the main axes of representational variation. Despite high dimensionality, over half of the explainable variance concentrated along two dominant axes: a continuum spanning objects of high biological salience, and a second integrating spatial context, physical scale, and manipulability. Importantly, neither reduced to a single semantic label, instead reflecting mixtures of visual and conceptual properties. Together they defined a triangular geometry, anchored by animal-, furniture- and food-related objects, stable across participants and two independent datasets, that mapped onto a lateral-to-medial cortical gradient, with category-selective regions emerging as local peaks within a broader continuum. These findings reveal that high-dimensional object representations in the ventral temporal cortex are structured by a small number of interpretable axes.

neuroscience↗

bioRxiv2026

Synonymous HTT CAA/CCA-loss variants associated with early Huntington disease onset enhance toxicity beyond somatic instability

Huntington disease is a fatal neurodegenerative disorder caused by CAG repeat expansion encoding polyglutamine in the HTT gene. Recent studies have shown that loss of CAA/CCA interruptions within polyglutamine-coding CAG tracts and adjacent polyproline-coding region are linked to earlier disease onset. It has been hypothesized that somatic repeat instability, influenced by these interrupted CAG tracts, may mediate this effect. Here we demonstrate that HTT CAA/CCA-loss variant linked to early disease onset exacerbates mutant HTT toxicity in cellular models through mechanisms independent of somatic repeat instability. The CAA/CCA-loss variant exhibits significantly higher toxicity than canonical HTT sequences in both transient expression and stable cell line models. Notably, this enhanced toxicity persists in knockout cells of the mismatch repair gene MSH3 where somatic instability is blunted, with a consistent toxicity hierarchy (CAA/CCA-loss > CCA-loss > CAA-loss > canonical HTT) in both wildtype and MSH3 knockout cells. Furthermore, the CAA/CCA-loss variant generates elevated levels of repeat-associated non-AUG (RAN) translation products. In HEK293-based cellular models, these results suggest that the disease-accelerating effects of HTT CAA/CCA-loss variants involve intrinsic properties of the altered sequence context, highlighting the importance of understanding sequence-specific mechanisms in HD pathogenesis beyond polyglutamine length and somatic instability.

genetics↗

bioRxiv2026

Unifying physical and molecular coordinate systems across modalities in spatial biology

Establishing a unified physical and molecular coordinate system from fragmented multi-modal data is a longstanding challenge in biology. Here, we present MAPS, a modality-agnostic platform for spatial biology comprising (1) MAPS-alignment for ultrafast alignment of any modality, (2) MAPS-integration for both anchored and unanchored integration across orthogonal modalities for 3D multi-modal reconstruction, and (3) MAPS-Explorer for large-scale interactive 3D analysis. MAPS outperformed existing methods across extensive benchmarks on 34 datasets spanning 16 technology platforms and 6 modalities, while delineating fine-grained multi-modal tissue architectures across diverse biological systems in mouse and human. At cross-consortium scale, MAPS integrated 434 slices comprising 21 million cells from 18 atlases and 5 modalities to construct the most comprehensive 3D multi-modal mouse brain atlas. At individual laboratory scale, MAPS empowered routine 2D spatial assays to reconstruct continuous 3D multi-modal landscapes of human hepatocellular carcinoma, revealing the limitations of 2D spatial relationships and uncovering depth-dependent immune-state transitions.

bioinformatics↗

bioRxiv2026

BioIMA: a one-click desktop tool for standardized extraction of phenotypic traits from biological images

Standardized extraction of quantitative phenotypes from images is increasingly important across plant biology, from ecological and evolutionary studies to genetics, breeding, and functional genomics. However, as large image datasets are increasingly used for trait analysis, many biologically relevant traits, including size, shape, color, and spatial patterning, are still measured manually or using fragmented semi-automated workflows. These limitations reduce throughput, reproducibility, and accessibility, especially for researchers without computational expertise. Here, we present BioIMA, an open-source desktop tool for rapid and standardized phenotyping from biological images. BioIMA integrates foundation model-based segmentation with automated trait computation, allowing users to extract quantitative measurements from images through an intuitive graphical interface and without model training. To validate its performance, we quantified a set of knot morphological traits in two Populus species, as these measurements are typically time-consuming to perform manually. Automatic measurements showed strong agreement with manual ImageJ-based measurements (R2 > 0.95), while reducing per-image processing time by approximately 75% (from ~15 s to ~4 s). BioIMA was further applied to diverse plant datasets, including Helianthus and Rhododendron images with varying morphologies and background conditions. Although developed for plant phenotyping, BioIMA may also be extended to other biological samples where region-based size, shape, or color traits are of interest. By combining accessibility and standardization in a lightweight local application, BioIMA provides a practical community resource for image-based phenotyping in ecological and evolutionary studies.

bioinformatics↗

bioRxiv2026

A modular architecture of human cellular aging across organs and diseases

Aging is a heterogeneous biological process in which different cellular systems undergo molecular remodeling at distinct rates, yet whether human cellular aging follows an organized architecture across organs remains unclear. Here, we integrate a multi-organ human single-cell transcriptomic atlas with plasma proteomic profiles from approximately 50,000 participants to reconstruct cellular aging states at population scale. By projecting cell-type-enriched molecular signatures onto circulating proteins, we characterize aging patterns across 128 organ-cell type pairs and identify 14 cellular aging modules comprising conserved cross-organ programs and organ-specific aging states. These modules reveal cellular identity as a dominant organizing axis of human aging that transcends anatomical boundaries. Module-level aging states uncover substantial inter-individual heterogeneity, with 34% of individuals exhibiting extreme aging deviation in at least one cellular module. Cellular aging modules exhibit distinct temporal trajectories, with structural and tissue-resident modules showing earlier remodeling than immune lineages. The modular organization of cellular aging is reflected in disease susceptibility, with accelerated aging of specific modules, particularly epithelial aging, showing broad associations with disease burden and mortality. Longitudinal analyses further demonstrate the stability and clinical relevance of cellular aging states, whereas lifestyle, metabolic and pharmacological factors show selective relationships with individual aging programs. Together, our study establishes a modular framework for understanding human cellular aging and reveals an organization of biological aging that may help explain individual differences in healthspan.

cell biology↗

bioRxiv2026

CD59 Promotes SNARE Complex Assembly via Interaction with the Proline-Rich N-Terminal Domain of VAMP2

ObjectiveThe complement regulatory protein CD59 has been shown to promote SNARE complex assembly, yet its interaction with vesicle-associated membrane protein 2 (VAMP2) remains poorly characterized. This study aims to identify the key domain in VAMP2 that mediates the CD59 interaction and to evaluate whether CD59 point mutations affect SNARE complex assembly. MethodsThe interaction between CD59 and VAMP2 was examined by immunofluorescence confocal microscopy and co-immunoprecipitation (co-IP). The effect of CD59 on SNARE complex assembly was assessed by co-expressing CD59 with the three core SNARE proteins (syntaxin-1, SNAP-25, and VAMP2) and detecting complex formation by western blotting. Four CD59 single-point mutants were generated and evaluated in SNARE assembly assays. AlphaFold3 was employed to predict the interaction between CD59 and individual VAMP2 domains (confidence threshold: ipTM + pTM [≥] 0.75). Truncated VAMP2 constructs were further characterized by molecular dynamics simulations and co-IP. Results(1) CD59 directly bound VAMP2 and promoted SNARE complex assembly without altering individual SNARE protein levels. (2) All four CD59 single-point mutants retained the ability to promote SNARE assembly at a level comparable to wild-type CD59, despite showing differential effects on binding stability in molecular dynamics simulations. (3) The proline-rich (P-rich) N-terminal domain of VAMP2 was identified as the key binding interface; its deletion abolished the CD59 interaction, whereas deletion of the SNARE motif did not. ConclusionCD59 promotes SNARE complex assembly through interaction with the P-rich N-terminal domain of VAMP2. The examined point mutations do not impair this function, suggesting that these sites may tolerate substitutions or that redundant contact residues maintain the interaction.

neuroscience↗

bioRxiv2026

Unscheduled DNA synthesis reveals a DNA repair hotspot and biomarker of somatic instability at the expanded-CAG repeat tract in the huntingtin gene

Somatic instability (SI) of expanded DNA repeats is a hallmark of repeat expansion disorder (REDs) and drives onset and progression in Huntingtons disease (HD) yet the absence of target engagement (TE) biomarkers for SI-modulating therapies represents a critical gap to clinical development. Here, we describe the development of the unscheduled repair synthesis assay (URSA)--combining 5-ethynyl-2-deoxyuridine (EdU) pulse-labeling with digital PCR or sequencing--and show that the CAG-expanded huntingtin (HTT) exon 1 allele is a highly active DNA repair hotspot in cells from people with HD (PwHD). Repair activity increases with repeat length, is allele-specific, and depends strongly on MSH3, a central driver of somatic expansion. URSA robustly quantifies MSH3 modulation in preclinical models within days compared to weeks or months required by conventional repeat-length measurements. Critically, substantial repair activity is detectable in peripheral blood mononuclear cells (PBMCs) from PwHD, where signal correlates with CAG length and improves predictive models of somatic expansion (SE) beyond age and CAG length alone. Unlike repeat-length changes, which require years to accumulate in blood, URSA signal is measurable within days. These findings establish DNA repair activity at the mutant HTT locus as a mechanistically grounded pharmacodynamic biomarker, enabling TE monitoring on a clinically actionable timescale, and with broad applicability to REDs and other diseases where modulation of the DNA damage response is therapeutically targeted.

neuroscience↗

bioRxiv2026

Surface architecture of the bacterial envelope determines phage adsorption route in pathogenic Escherichia coli O157:H7

The outermost surface layers of Gram-negative bacteria determine phage access to terminal receptors, yet their genetic basis has been mapped almost exclusively in laboratory strains that lack them. Here we apply genome-wide RB-TnSeq fitness profiling to four Escherichia coli O157:H7 strains from distinct phylogenetic clades sharing the O157 O-antigen, using 38 phages with terminal receptors previously mapped in E. coli K-12 strain. RB-TnSeq fitness landscapes across all four pathogenic backgrounds were mostly similar, and dominated by surface-associated loci, including the gfc-etk group 4 capsule operon, O-antigen biosynthesis genes, LPS core assembly genes and outer membrane proteins. Disruption of gfc-etk abolished infection in 11 genetically diverse myoviruses, establishing the O-antigen capsule as a widespread required primary recognition substrate. O-antigen loci generated two classes of fitness score patterns. For 10 phages, disruption increased infectivity, indicating it is a barrier to receptor access; for 3 others, disruption abolished infectivity, demonstrating it can also be a primary recognition substrate. Outer membrane protein receptor identity was conserved across laboratory and pathogenic backgrounds, with the same proteins recognized in both K-12 and O157:H7, while glycan layer state determines whether these receptors are reached. These results demonstrate that outer surface glycan layers can act as primary and optional recognition substrates for phage infection, or as physical barriers preventing terminal receptor access. Extending the ability to probe phage-targeted receptors beyond outer membrane proteins provides a framework for incorporating glycan layer state into predictive models of phage-host interactions.

microbiology↗

bioRxiv2026

A sensitive bioassay for detecting Plasmodiophora brassicae in canola field soils

We describe a biodegradable-cup bioassay for detecting viable Plasmodiophora brassicae in soil samples. Soil samples either artificially inoculated with P. brassicae resting spores or collected from canola fields were aliquoted into biodegradable cups containing 20 g of soil per cup. Two cups representing the same soil sample or inoculum concentration were placed in each pot filled with Sunshine Mix. Six seeds of the canola cultivar Westar were sown into each cup and thinned to four seedlings per cup ten days after planting. After four weeks, roots were examined for the presence of clubroot galls. Across three independent inoculated-soil experiments, galls were observed in samples containing as few as 1 resting spore g-1 soil. In contrast, under a qPCR assay evaluated in parallel, consistent amplification across three technical replicates was obtained only at 100 resting spores g-1 soil or greater. In field samples, the bioassay produced galls from 11 qPCR-positive samples and seven of ten qPCR-negative samples. Although the bioassay is not intended for rapid diagnosis or direct quantification, it provides a practical tool for annual clubroot surveys and for studies requiring recovery, propagation, or characterization of viable P. brassicae from soil samples collected across diverse geographic regions.

microbiology↗

bioRxiv2026

Peri-Locus Coeruleus Controls Endothelial Cell Heterogeneity in Enriched Environments via Region-Specific Norepinephrine Signaling

The brain acts as a central integrator that enables organisms to interpret environmental stimuli and coordinate adaptive responses across the body. While enriched environments are known to enhance neural plasticity and cognitive function, their impact on peripheral organ systems remains less understood. Here, we show that enriched environmental conditions activate a peri-locus coeruleus (peri-LC) neuronal ensemble that preserves CD31hiEMCNhi type H endothelium, a specialized bone-associated endothelial subtype, against age-associated decline, thereby enhancing femoral bone density. Chemogenetic activation and ablation experiments further revealed that this peri-LC ensemble is functionally distinct from other sympathetic regulatory brain regions in its control of bone endothelial heterogeneity and skeletal mass. Three-dimensional bone clearing and spatial analyses showed that CD31hiEMCNhi endothelium is closely associated with sympathetic nerve terminals. The peri-LC mediates this process through sympathetic signaling and {beta}2-adrenergic receptors on bone vascular endothelial cells. In vivo imaging further demonstrated that norepinephrine release is spatially restricted, with sprouting endothelial cells near the growth plate exhibiting the highest sensitivity. Together, these findings reveal a refined brain-periphery regulatory logic in which distinct sympathetic brain circuits engage spatially restricted norepinephrine signaling to coordinate organ-specific vascular and skeletal adaptations.

neuroscience↗

bioRxiv2026

MALDI Tandem Mass Spectrometry for Colony-Based Dereplication of Natural Products

Microbial libraries remain an important resource for natural product discovery; however, constructing taxonomically and chemically diverse collections remains a challenge. Advances in dereplication strategies, including molecular networking, have reduced the rediscovery of known bioactive molecules and facilitated the identification of novel chemical scaffolds, but these approaches are typically applied after library construction or to existing repositories. Furthermore, many dereplication workflows require scaled fermentation and extraction, increasing the time needed to assess a microbes metabolite profile. Here, we integrate matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) into the bioinformatics platform IDBac, enabling streamlined characterization of microbial taxonomic identity, metabolite production potential, and preliminary metabolite annotation through GNPS2 molecular networking. This miniaturized high-content workflow facilitates strain prioritization by providing metabolite annotations directly from single microbial colonies prior to scale-up and extraction. Application of this approach to marine actinomycetes enabled the annotation of lavanducyanin and multiple napyradiomycin analogs. Subsequent investigation led to the discovery of napyradiomycin B8 from marine Streptomyces sp. CNZ-289, which was confirmed by 1D and 2D NMR spectroscopy and MALDI-MS/MS. Expanding this workflow to an untargeted analysis of 25 commensal marine vertebrate-derived bacterial isolates resulted in the annotation of several known bioactive natural products, including surugamides, antimycins, desferrioxamine siderophores, and the isolation and elucidation of harmane derivatives using NMR. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/733640v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@c92cfforg.highwire.dtl.DTLVardef@1a9522borg.highwire.dtl.DTLVardef@151b309org.highwire.dtl.DTLVardef@c1531f_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2026

Homeobox transcription factor MSX2 down-regulates ERα action to facilitate anti-estrogensensitivity in ERα+ breast cancer

Breast cancer is the most common malignancy among women worldwide. Estrogen receptor (ER)-positive breast cancer is about 70% in the total breast cancer. It has variable prognosis and high recurrent risk, frequently developing resistance to endocrine therapies. Herein, we have identified that a homeobox transcription factor MSX2 downregulated in ER-positive breast cancer is correlated with the advanced grade and poor survival outcomes. Our results have demonstrated that MSX2 interacts with ER to inhibit ER-mediated transactivation. Mechanistically, MSX2 associates with HDAC1/HDAC2 to form a protein complex. MSX2 is required for recruitment of HDAC1/HDAC2 complex to estrogen response elements (EREs) region on ER downstream target genes, reducing histone H3K9ac and H3K27ac levels to inactivate gene transcription. Functionally, ectopic expression of MSX2 suppresses cell growth and enhances the sensitivity to anti-estrogen treatment in ER-positive breast cancer cells. Our results indicate that MSX2 as a novel co-repressor of ER is involved in suppression of ER-positive breast cancer progression. Restoring MSX2 protein may provide a promising strategy to overcome endocrine resistance in ER-positive breast cancer.

Molecular Biology↗

bioRxiv2026

Functional ultrasound imaging reveals pathway-specific visual system reorganization in young Cln3-/- mice

CLN3 disease, or juvenile Batten disease, is a neurodegenerative lysosomal storage disorder in which visual impairment is typically the earliest clinical manifestation. Although retinal pathology has been extensively studied, functional alterations within central visual pathways remain poorly understood. Here, we used functional ultrasound (fUS) imaging to characterize visually evoked activity across central visual circuits in young Cln3 knockout (Cln3-/-) mice before the onset of severe retinal degeneration. Visually evoked hemodynamic responses were quantified in regions spanning the geniculostriate and extrageniculate visual pathways, including cortical, thalamic, and midbrain regions. To assess regional pathological burden, accumulation of subunit c of mitochondrial ATP synthase (SCMAS), a pathological marker of CLN3 disease, was examined using immunohistochemistry. We found that Cln3-/- mice exhibited pathway-specific alterations in visually evoked activity. Regions along the extrageniculate pathway, including the midbrain, posterior thalamus, and anterior secondary visual cortex, showed enhanced activation relative to wild-type controls. In contrast, activation within the geniculostriate pathway was reduced in the anterior thalamus and remained unchanged in the primary and posterior secondary visual cortex. SCMAS accumulation was elevated across all examined visual regions in Cln3-/- mice relative to wild-type controls, with greater accumulation observed in geniculostriate regions than in extrageniculate regions. These findings demonstrate early pathway-specific functional and pathological alterations in the visual system of Cln3-/- mice, suggesting pathway-level reorganization of central visual processing. This study advances understanding of central visual dysfunction in CLN3 disease and highlights fUS imaging as a sensitive approach for detecting early functional abnormalities in neurodegenerative disorders.

neuroscience↗

bioRxiv2026

Cyclin C nuclear release and mitochondrial dysfunction define molecular signatures of MED13L Syndrome

The Mediator Kinase Module (MKM) coordinates transcriptional programs regulating cellular metabolism, stress responses, and differentiation. Heterozygous variants of MED13L, a core MKM component, cause a neurodevelopmental disorder characterized by variable intellectual disability, developmental delay, neuromuscular dysfunction, and congenital anomalies. However, the molecular basis underlying this clinical heterogeneity is poorly defined. Previously, we identified mitochondrial dysfunction and aberrant nuclear release of another MKM component, cyclin C (CCNC), in a single MED13L syndrome patient-derived fibroblast line. Here, we expand these studies across 12 patient-derived fibroblasts harboring 11 distinct MED13L variants. We identify mitochondrial dysfunction as a consistent feature of MED13L variation, characterized by reduced mitochondrial ATP production, decreased mitochondrial DNA abundance, elevated reactive oxygen species, and impaired transcription of genes involved in mitochondrial biogenesis. In parallel, all variant lines exhibit aberrant cytoplasmic CCNC localization, consistent with its established role in mitochondrial fission. Longitudinal analyses further reveal progressive declines in mitochondrial function associated with premature cellular aging, consistent with increased metabolic deficits. Importantly, the severity of mitochondrial dysfunction shows an association with variant position within MED13L and with clinical functional measures, suggesting that mutation location may partially predict disease severity. Together, these findings establish mitochondrial dysfunction as a consistent cellular feature of MED13L heterozygosity and identify CCNC mis-localization as a candidate biomarker of MKM disruption. More broadly, this work reveals an intersection between transcriptional control and mitochondrial homeostasis in MED13L syndrome, forming the framework for biomarker-driven therapeutic development in MED13L-associated and related neurodevelopmental disorders.

genetics↗

bioRxiv2026

Distinct Auditory Thalamocortical Pathologies Underlie Emerging Neurophysiological Dysfunction in a Cln3 Mouse Model of Batten Disease

CLN3 disease, the most common form of the Neuronal Ceroid Lipofuscinoses (NCLs), causes progressive cognitive decline and language impairment in humans. A pathological hallmark is the accumulation of storage material within neuronal lysosomes resulting from mutations in the CLN3 gene. We previously identified parallel deficits in auditory duration mismatch negativity (MMN), an electroencephalography (EEG)-based marker of auditory change detection, in individuals with CLN3 disease and in Cln3-/- mice. MMN-dependent auditory change detection relies on sensory-memory comparison mechanisms. However, the anatomical and neurophysiological substrates underlying this response in CLN3 disease remain unclear. Here, we investigated central auditory dysfunction in Cln3-/- mice by integrating immunohistochemical mapping of lysosomal storage pathology, using the canonical marker Subunit C of Mitochondrial ATP Synthase (SCMAS), with EEG analysis of auditory evoked potentials (AEPs). Neuropathological analyses revealed age-dependent and sex-divergent SCMAS accumulation across the auditory thalamocortical circuit, including the excitatory auditory thalamus, the inhibitory thalamic reticular nucleus, and the primary auditory cortex. In parallel, Cln3-/- mice exhibited age- and sex-dependent alterations in AEPs relative to wild-type controls. Importantly, an integrated measure of auditory thalamocortical SCMAS accumulation accounted for a substantial portion of age- and sex-matched variation in AEP responses, with stronger associations for the early N1 component than the later MMN component. Together, these findings link age-dependent and sex-divergent auditory neurophysiological deficits to region-specific lysosomal storage pathology within the auditory thalamocortical circuit in the Cln3-/- mouse model. This integrated functional-anatomical framework provides insight into circuit vulnerability and supports the development of translational neurophysiological biomarkers for CLN3 disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/729359v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8dc148org.highwire.dtl.DTLVardef@8c918borg.highwire.dtl.DTLVardef@a7483dorg.highwire.dtl.DTLVardef@77d171_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISCMAS accumulates across the auditory thalamocortical circuit in Cln3-/- mice C_LIO_LIAccumulation shows distinct age- and sex-dependent regional trajectories C_LIO_LICln3-/- mice exhibit progressive alterations in auditory evoked potentials C_LIO_LIThalamic pathology is strongly associated with the early auditory N1 response C_LIO_LIHistology-EEG integration links circuit pathology to auditory dysfunction C_LI

neuroscience↗