Biology subjects

Hill, E.

Publications and source records attributed to Hill, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Lysyl oxidase drives ccRCC progression by coordinating HIF-2α transcription program with tumor microenvironment

Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2 transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2 by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2 G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2 in high-grade patient tumors. Together, LOX coordinates HIF-2 transcription program with TME and is a therapeutic target in ccRCC.

cancer biology↗

bioRxiv2026

FusedFCR: A Fused Forward Continuation-Ratio model for marker selection along cell-fate trajectories

Time-course single-cell RNA sequencing (scRNA-seq) data collected across ordered stages provide population-level snapshots of differentiation, disease progression, and aging. Supervised pseudotime methods use observed stage labels to reconstruct continuous progression but generally do not identify marker genes associated with changes from one stage to the next. Unsupervised pseudotime-based marker selection methods infer latent trajectories directly from expression data and identify trajectory-associated genes, but do not explicitly link these associations to the observed stages. We propose FusedFCR, a regularized forward continuation-ratio model that represents cellular progression through a sequence of conditional transitions across ordered stages. FusedFCR combines a lasso penalty for gene selection with a fusion penalty that encourages similar effects across adjacent transitions while allowing transient and direction-changing associations. The resulting transition-specific coefficients support interpretable gene selection and a continuous pseudotime-like projection anchored to the observed developmental stages. In simulations, FusedFCR accurately recovers gene-effect trajectories and improved predictive performance relative to alternative methods. Applied to one mouse and three human datasets (mouse pancreatic beta-cells, human extravillous trophoblast, human induced pluripotent stem cell derived astrocytes, and human endometrial cells during the secretory phase), FusedFCR identifies biologically interpretable genes associated with distinct developmental transitions. Gene set enrichment analysis further reveals stage-specific pathway activity consistent with known developmental biology, while held-out stage-classification accuracy was competitive or superior across both datasets. Together, these results show that FusedFCR complements pseudotemporal ordering by identifying which molecular programs change and when those changes emerge along the developmental trajectory. An accompanying R package is available on GitHub.

bioinformatics↗

bioRxiv2025

Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) features CTE-like tau seeds in brain and spinal cord

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disorder that was once hyperendemic in the island of Guam (Mariana Islands, US) and a few other Pacific locales. Despite extensive investigations into its origins, the etiology of ALS/PDC remains unclear. ALS/PDC is, at the neuropathology level, characterized by tau-dominant multiple proteinopathy in brain and spinal cord. It was recently reported that Guam ALS/PDC brain extracts exhibit tau seeding activity in fluorescence resonance energy transfer (FRET)-based biosensor cells. To build upon those findings and explore the nature of tau seeds in ALS/PDC in more detail, we used an alanine mutational scanning (Ala scan) approach to determine the seeding profile of tau in nervous tissues of Guam ALS/PDC cases. First, we confirmed the detection of tau seeding activity in ALS/PDC brain samples in tau biosensor cells. Notably, we could also detect potent tau seeding activity in spinal cord. Subsequent Ala scan assays demonstrated that ALS/PDC tau displays an aggregate incorporation pattern that resembles that of chronic traumatic encephalopathy (CTE)-type tau. This result is consistent with recent electron cryo-microscopy studies of tau, which revealed that ALS/PDC tau filaments are predominantly of the CTE-type. The structural characteristics and seeding behavior of ALS/PDC tau, as well as the regional distribution of tau pathology at post-mortem, suggest that ALS/PDC is a CTE-like tauopathy. Significance StatementNeurodegenerative tauopathies are characterized by proteinaceous deposits containing microtubule-associated tau in nervous tissue. Emerging evidence suggests that disease-associated tau proteins adopt abnormal, self-propagating conformations characteristic of prions. Here, we employed alanine mutational scanning (Ala scan) to determine the nature of prion-like tau seeds in ALS/PDC, a mysterious disorder that occurred formerly in high incidence in certain regions in the western Pacific. We show that the Ala scan incorporation profile of ALS/PDC tau is similar to that of abnormal tau proteins in chronic traumatic encephalopathy (CTE). The findings lend support to the idea that ALS/PDC can be classified structurally as a CTE-like tauopathy. This work may have important implications for our understanding of ALS/PDC as well as common neurological disorders beyond the Pacific.

neuroscience↗

bioRxiv2025

GRASS-NB: Group-structured variable selection for spatial negative binomial data with applications to cancer registry and spatial omics

Spatially structured, overdispersed count data with high-dimensional predictors are increasingly observed across studies from population-level epidemiology to cellular-level spatial omics. Feature selection is critical to identify influential predictors, such as key risk factors or biomarkers. Few Bayesian studies have assessed negative binomial regression (NBR) models with standard variable selection priors, like the mixture spike-and-slab (SS) or continuous horseshoe (HS), but mostly under aspatial settings. Features often form groups; for instance, in population surveys, caloric intake and physical activity may fall under "Diet & Exercise", while cigarette use and smoking laws belong to "Smoking". We propose a flexible NBR model that accommodates spatial autocorrelation and introduces a novel group-structured prior by hybridizing SS and HS shrinkage. The models performance with different priors is evaluated in terms of specificity, precision, and computational cost under challenging scenarios, including "large p, small n" cases. We further apply the model to CDC state-level cancer data, comprising demographic, screening, and behavioral covariates, to identify key drivers and population-level risk factors, and to a melanoma spatial omics dataset for predictive modeling expression of gene. An efficient R package is provided on GitHub.

bioinformatics↗

bioRxiv2025

Lower Bound Estimates for Electrophysiological Power Dissipation in Human Gray Matter

The human brain is popularly described as remarkably energy efficient, with its metabolic power consumption estimated at approximately 20 watts (W). Biophysical models have partitioned this power budget across distinct cellular processes, but these theoretical estimates have yet to be empirically constrained using whole-brain electrophysiological data. Here, we used magnetoencephalography (MEG) source imaging of resting-state human brain activity to derive empirical lower-bound estimates of electrical power dissipation in cortical gray matter. We found that the total power dissipated by currents, primarily associated with post-synaptic potentials, ranges between 10-9 and 10-10 W, several orders of magnitude lower than prevailing metabolic estimates. Using finite element modeling (FEM), we observed that electrophysiological power dissipation is predominantly confined to gray matter. Additionally, spatial variations in MEG-derived power dissipation partially correlated with regional oxygen metabolism measured by PET, yet notable discrepancies emerged across large-scale functional brain networks. These results underscore a critical divergence between electrophysiological and metabolic indices of brain energy use, and highlight the need for more integrated biophysical models to bridge this gap and better characterize the physiological underpinnings of regional brain energetics.

neuroscience↗

bioRxiv2025

Insights from U.S. beekeeper triage surveys following unusually high honey bee colony losses 2024-2025

In January of 2025, U.S. commercial beekeepers reported unusually high honey bee colony losses as they prepared colonies for almond pollination. Two industry groups launched nationwide surveys to document colony losses between June 2024 and March 2025 across all scales of beekeeping. This study analyzes these survey data to assess colony losses, estimate financial impacts, and identify correlations with beekeeper management practices and geographical locations. Unlike past surveys, commercial beekeepers experienced more severe losses than smaller-scale beekeepers during this period. Respondents, managing over half of U.S. colonies, most frequently cited Varroa mites as the cause for their losses. Varroa mites were followed by pesticides and pathogens in the case of commercial beekeepers and by queen failure and weather in the case of smaller-scale beekeepers. Although Varroa was the most frequently cited cause, losses did not significantly differ between users and non-users of amitraz, suggesting that rising amitraz resistance alone does not explain observed trends. Differences in protein and carbohydrate feeding frequencies also played a role in net losses. While colony loss rates and financial concern varied widely among respondents, commercial beekeepers understandably showed higher sensitivity to financial impacts, with concerns increasing linearly with loss severity. This study highlights the value of beekeeper surveys which, alongside direct analyses of bee samples and longitudinal studies, help identify effective management strategies and environmental risks. Such insights are crucial for addressing the leading causes of colony losses on a national scale, and ultimately aid in safeguarding honey bee health, pollination services, and agricultural production. HighlightsO_LIUnprecedented honey bee colony losses C_LIO_LIIndications of disease stress C_LIO_LIHigh economic pain for commercial beekeepers and growers C_LI

ecology↗

bioRxiv2025

Modular cyanobacterial regulatory architecture enables dynamic graded responses to oxidative stress

A fundamental paradox of oxygenic photosynthesis: growth-essential energy machinery generates reactive oxygen species (ROS) threatening survival, yet the systems-level regulatory networks balancing the growth-survival trade-off remain unclear. Through integrative experimental-computational analysis combining steady-state transcriptomics with independent component analysis across 0-78.4% oxygen, we decoded the regulatory architecture driving progressive transitions in Synechococcus elongatus PCC 7942 from ROS sensing through defense to growth shutdown. Integration of 407 transcriptome samples identified 78 regulatory modules (iModulons) explaining 72.3% of expression variance and revealed calibrated responses: low stress triggers metalloregulators (SufR, PerR) for ROS sensing and primary antioxidants; moderate stress activates RpaB operating through four distinct regulatory states redirecting metabolism to defense; severe stress induces growth arrest via stringent response pathway convergence. This quantitative regulatory framework enables precise growth-defense calibration through modular network architecture: RpaB coordinates genome-wide resource reallocation (RpaB[~]P growth-promoting, RpaB ROS defense-activating, RpaABC circadian-integrating, RpaB ycf46 checkpoint activation), offering systematic strategies for engineering stress-tolerant bioplatforms and predictive models for environmental stress responses.

systems biology↗

bioRxiv2025

Viruses and vectors tied to honey bee colony losses

Commercial beekeepers in the US reported severe colony losses early in 2025, as colonies were being staged for their critical role in the almond pollination season in California. Average reported losses since the preceding spring exceeded 60%, with substantial variation among operations. Many colonies were still actively collapsing in January, 2025, when pooled and individual samples were collected then screened for levels of known honey bee pathogens and parasites. Deformed wing virus strains A and B, along with Acute bee paralysis virus, were found at unusually high levels, either in pooled colony samples or in individual bees exhibiting shaking behaviors and morbidity. Differences between these two analyses suggest that direct collections of morbid bees provide a superior diagnostic for causal viruses, a suggestion borne out by confirmation of symptoms and morbidity following isolation and new inoculations. Since these viruses are known to be vectored by parasitic Varroa mites, mites from collapsed colonies were in turn screened for resistance to amitraz, a critical miticide used widely by beekeepers. Miticide resistance was found in all collected Varroa, underscoring the urgent need for new control strategies for this parasite. While viruses are a likely end-stage cause of colony death, other stressors such as nutritional stress and agrochemicals may have also played significant roles.

ecology↗

bioRxiv2025

CO2 sensitive connexin channel synapses in the VTA release 5HT to regulate dopaminergic neurons

Hypercapnic arousal is a life-preserving reflex that promotes awakening in response to elevated PCO2, yet the cellular mechanisms by which CO2 is detected remain incompletely understood. Serotonergic neurons of the dorsal raphe (DR) have been implicated in hypercapnic responses, but the molecular sensor that directly detects CO2 within this circuit is unknown. Here, we show that the CO2-gated connexin 26 (Cx26) hemichannel is expressed on serotonergic terminals projecting from the DR to the ventral tegmental area (VTA). Brief elevations in PCO2 modulated the excitability of VTA dopamine neurons through serotonergic signaling without altering glutamatergic transmission, and these effects were abolished by pharmacological inhibition of hemichannels. By expressing Cx26 and genetically encoded GRAB5HT sensors in cultured cells, we further demonstrate that Cx26 hemichannels opened by elevated PCO2 are directly permeable to serotonin. Selective removal of CO2 sensitivity from Cx26 in DR serotonergic neurons delayed arousal from sleep during transient hypercapnia and reduced activation of VTA dopamine neurons in vivo. Together, these findings identify Cx26 hemichannels as a direct CO2 sensor that enables serotonin release through a channel co-synapse and contributes to hypercapnic arousal.

neuroscience↗

bioRxiv2025

Transcriptome analysis of the winter tick (Dermacentor albipictus) reveals sex-specific expression patterns

The winter tick, Dermacentor albipictus, is a significant ectoparasite of ruminants across North America, posing health risks to wildlife and occasionally humans. Despite its ecological importance, limited genomic resources exist for this species. This study provides the first comprehensive transcriptome analysis of D. albipictus, focusing on early-stage embryos, sexed adults, dissected ovaries, and dissected male reproductive systems. Differential gene expression analyses revealed significant sex-biased expression patterns, and functional annotations identified candidate genes involved in sex determination. Notably, we identified the first documented case of sex-specific splicing of a doublesex-like gene in chelicerates, a mechanism previously thought to be absent in this group. This discovery suggests that ticks may share more insect-like features of sexual differentiation, with implications for understanding the evolution of sex determination pathways in arthropods These transcriptome data serve as a critical resource for understanding the biology of D. albipictus and will facilitate the development of novel genetic control strategies.

genomics↗

bioRxiv2025

Intracellular Trafficking SNARE Protein, Syntaxin-6, is a Modifier of Prion and Tau Pathogenesis in vivo and in Cellular Models

Syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk factor for sporadic prion disease, progressive supranuclear palsy and Alzheimers disease. However, no study has validated its functional role in these diseases, explored the disease stage at which it is acting nor its mechanism of action. Here, we show that syntaxin-6 acts at early stages of prion disease in experimental mice by increasing disease transmission risk following inoculation with low prion doses. Conversely, syntaxin-6 does not affect prion propagation kinetics or toxicity during established disease. Syntaxin-6 manipulation in cellular models profoundly alters the subcellular distribution and morphologies of disease-related PrP and modifies prion export. Furthermore, syntaxin-6 knockout in a transgenic tauopathy mouse model exerts protective effects on numerous physiological, behavioural and neuropathological outcome measures. Therefore, our studies firmly establish syntaxin-6 as a modifier of prion and tau pathogenesis, providing key insights into a fundamental mechanism of neurodegeneration.

neuroscience↗

bioRxiv2025

Engineering of CRISPR-Cas PAM recognition using deep learning of vast evolutionary data

CRISPR-Cas enzymes must recognize a protospacer-adjacent motif (PAM) to edit a genomic site, significantly limiting the range of targetable sequences in a genome. Machine learning-based protein engineering provides a powerful solution to efficiently generate Cas protein variants tailored to recognize specific PAMs. Here, we present Protein2PAM, an evolution-informed deep learning model trained on a dataset of over 45,000 CRISPR-Cas PAMs. Protein2PAM rapidly and accurately predicts PAM specificity directly from Cas proteins across Type I, II, and V CRISPR-Cas systems. Using in silico deep mutational scanning, we demonstrate that the model can identify residues critical for PAM recognition in Cas9 without utilizing structural information. As a proof of concept for protein engineering, we employ Protein2PAM to computationally evolve Nme1Cas9, generating variants with broadened PAM recognition and up to a 50-fold increase in PAM cleavage rates compared to the wild-type under in vitro conditions. This work represents the first successful application of machine learning to achieve customization of Cas enzymes for alternate PAM recognition, paving the way for personalized genome editing.

synthetic biology↗

bioRxiv2024

An evolutionarily conserved Hox-Gbx segmentation code in the rice coral Montipora capitata

Segmentation of the gastric cavity is a synapomorphic trait of cnidarians of the class Anthozoa (corals and sea anemones), with different clades forming distinct numbers of segments. In the starlet sea anemone Nematostella vectensis, for example, eight bilaterally positioned gastric segments are generated by the action of a group of Hox-Gbx genes in the developing larval endo-mesoderm. Still, given the range of segment numbers observed in different anthozoans, it remains unclear whether this Hox-Gbx module is evolutionarily conserved and how it might be deployed to generate different numbers of segments. Here, we systematically interrogate the role of Hox-Gbx genes during development of the rice coral Montipora capitata. We first characterize the temporal sequence of segmentation in M. capitata juveniles and then combine transcriptomic profiling and in situ hybridization to identify three conserved homeobox-containing genes, McAnthox8, McAnthox6a.1 and McGbx, which are collectively expressed in the developing endo-mesoderm prior to and during segment formation. The expression boundaries of these genes prefigure the positions of the first six segment boundaries, similar to their Nematostella homologs. Further, we show that chemical inhibition of BMP activity at the planula stage abolishes the expression of Hox-Gbx genes, leading to the formation of an unsegmented gastric cavity. These findings demonstrate the existence of a functionally conserved Hox-Gbx module in evolutionarily divergent anthozoan species, suggesting that the last common ancestor of all anthozoans likely utilized a similar genetic toolkit to axially pattern the endo-mesoderm into metameric subunits.

evolutionary biology↗

bioRxiv2024

Adapting protein language models for structure-conditioned design

Generative models for protein design trained on experimentally determined structures have proven useful for a variety of design tasks. However, such methods are limited by the quantity and diversity of structures used for training, which represent a small, biased fraction of protein space. Here, we describe proseLM, a method for protein sequence design based on adaptation of protein language models to incorporate structural and functional context. We show that proseLM benefits from the scaling trends of underlying language models, and that the addition of non-protein context - nucleic acids, ligands, and ions - improves recovery of native residues during design by 4-5% across model scales. These improvements are most pronounced for residues that directly interface with non-protein context, which are faithfully recovered at rates >70% by the most capable proseLM models. We experimentally validated proseLM by optimizing the editing efficiency of genome editors in human cells, achieving a 50% increase in base editing activity, and by redesigning therapeutic antibodies, resulting in a PD-1 binder with 2.2 nM affinity.

bioengineering↗

bioRxiv2024

Design of highly functional genome editors by modeling the universe of CRISPR-Cas sequences

Gene editing has the potential to solve fundamental challenges in agriculture, biotechnology, and human health. CRISPR-based gene editors derived from microbes, while powerful, often show significant functional tradeoffs when ported into non-native environments, such as human cells. Artificial intelligence (AI) enabled design provides a powerful alternative with potential to bypass evolutionary constraints and generate editors with optimal properties. Here, using large language models (LLMs) trained on biological diversity at scale, we demonstrate the first successful precision editing of the human genome with a programmable gene editor designed with AI. To achieve this goal, we curated a dataset of over one million CRISPR operons through systematic mining of 26 terabases of assembled genomes and meta-genomes. We demonstrate the capacity of our models by generating 4.8x the number of protein clusters across CRISPR-Cas families found in nature and tailoring single-guide RNA sequences for Cas9-like effector proteins. Several of the generated gene editors show comparable or improved activity and specificity relative to SpCas9, the prototypical gene editing effector, while being 400 mutations away in sequence. Finally, we demonstrate an AI-generated gene editor, denoted as OpenCRISPR-1, exhibits compatibility with base editing. We release OpenCRISPR-1 publicly to facilitate broad, ethical usage across research and commercial applications.

synthetic biology↗

bioRxiv2023

SpaceANOVA: Spatial co-occurrence analysis of cell types in multiplex imaging data using point process and functional ANOVA

MotivationMultiplex imaging platforms have enabled the identification of the spatial organization of different types of cells in complex tissue or tumor microenvironment (TME). Exploring the potential variations in the spatial co-occurrence or co-localization of different cell types across distinct tissue or disease classes can provide significant pathological insights, paving the way for intervention strategies. However, the existing methods in this context either rely on stringent statistical assumptions or suffer from a lack of generalizability. ResultsWe present a highly powerful method to study differential spatial co-occurrence of cell types across multiple tissue or disease groups, based on the theories of the Poisson point process (PPP) and functional analysis of variance (FANOVA). Notably, the method accommodates multiple images per subject and addresses the problem of missing tissue regions, commonly encountered in such a context due to the complex nature of the data-collection procedure. We demonstrate the superior statistical power and robustness of the method in comparison to existing approaches through realistic simulation studies. Furthermore, we apply the method to three real datasets on different diseases collected using different imaging platforms. In particular, one of these datasets reveals novel insights into the spatial characteristics of various types of precursor lesions associated with colorectal cancer. AvailabilityThe associated R package can be found here, https://github.com/sealx017/SpaceANOVA. Contactsealso@musc.edu Supplementary informationThe supplementary material is attached.

bioinformatics↗

bioRxiv2023

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

Alzheimers disease (AD) and other tauopathies are characterized by the aggregation of tau into soluble and insoluble forms (including tangles and neuropil threads). In humans, a fraction of both phosphorylated and non-phosphorylated N-terminal to mid-domain tau species, including the aggregated forms, are secreted into cerebrospinal fluid (CSF). Some of these CSF tau species can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. While in animal models of AD pathology, soluble tau aggregates have been shown to disrupt neuronal function, it is unclear whether the tau species present in CSF will modulate neural activity. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. The method involves incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF, followed by a suite of electrophysiological recording methods to evaluate their effects on neuronal function from single cells through to the network level. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, has enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input-output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/525362v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@13f564forg.highwire.dtl.DTLVardef@13b75cborg.highwire.dtl.DTLVardef@b27dbaorg.highwire.dtl.DTLVardef@5c68c0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Knockout of Sporadic Creutzfeldt-Jakob Disease Risk Gene Stx6 in Mice Extends Prion Disease Incubation Time

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimers disease. Author SummarySporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is an invariably fatal disease with no established disease-modifying treatments. The identification of STX6 as a proposed risk gene for sCJD motivated the generation of a new mouse knockout model, in which we found no grossly deleterious phenotypes. A transmission study in Stx6-/-, Stx6+/- and Stx6+/+ mice challenged with two prion strains showed reduced syntaxin-6 expression is associated with a modest prolongation of prion disease incubation periods, supporting a pathological role of Stx6 expression in prion disease pathogenesis. Syntaxin-6 appears to have pleiotropic risk effects across multiple neurodegenerative diseases including progressive supranuclear palsy and Alzheimers disease. Thus, this work supports further exploration of the STX6 susceptibility mechanism, which likely has relevance across multiple neurodegenerative diseases.

neuroscience↗