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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 451 records · Page 25Linked to original sources

bioRxiv2025

Sex-specific effects of fecal microbiota transplantation on TBI-exacerbated Alzheimer's pathology in mice

BackgroundTraumatic brain injury (TBI) accelerates Alzheimers disease (AD) pathology and neuroinflammation, potentially via gut-brain axis disruptions. Whether restoring gut microbial homeostasis mitigates TBI-exacerbated AD features remains unclear, particularly with respect to sex differences. ObjectiveThe goal of our study was to test whether fecal microbiota transplantation (FMT) modifies amyloid pathology, neuroinflammation, gut microbial composition, metabolites, and motor outcomes in male and female 5xFAD mice subjected to TBI. MethodsMale and female 5xFAD mice received sham treatments or controlled cortical impact, followed 24 hours later by vehicle (VH) or sex-matched FMT from C57BL/6 donors. Assessments at baseline, 1, and 3 days post-injury included Thioflavin-S and 6E10 immunostaining for A{beta}, Iba-1 and GFAP for glial activation, lesion volume, rotarod performance, 16S rRNA sequencing for microbiome profiling, serum short-chain fatty acids (SCFAs), and gut histology. ResultsTBI increased cortical and dentate gyrus A{beta} burden, with females showing greater vulnerability. FMT reduced A{beta} deposition in sham animals and shifted plaque morphology but did not attenuate TBI-induced amyloid escalation. FMT differentially modulated glial responses by sex and region (reduced microgliosis in males) without altering lesion volume. Rotarod performance was better in sham females compared to males and declined in FMT-treated TBI females. Fecal microbiome alpha diversity and richness were unchanged, while beta diversity revealed marked, time-dependent community shifts after TBI that were slightly altered by FMT. Gut morphology remained broadly intact, but crypt width increased after TBI, particularly in males. ConclusionIn 5xFAD mice, TBI drives sex-dependent worsening of amyloid pathology, neuroinflammation, and dysbiosis. Acute FMT partially restores microbial composition and plaque features in sham animals but fails to reverse TBI-induced neuroinflammation or motor deficits. These findings underscore the context- and sex-dependence of microbiome interventions and support longer-term, sex-specific strategies for AD with comorbid TBI.

neuroscience↗

bioRxiv2025

Patient-derived lymphocytes drive smoldering lesion pathology in a chimeric multiple sclerosis mouse model

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination, axonal injury, and neurodegeneration. Smoldering lesions-- defined by an inactive core, poor remyelination, and a rim of chronically activated microglia-- are hallmarks of a progressive disease course and correlate with irreversible disability. The mechanisms driving their formation remain poorly understood. Using a chimeric mouse model, we investigated the long-term impact of healthy donors (HD) and MS patient-derived lymphocytes (LY) graft on the evolution of spinal cord demyelinated lesion. Three months post-grafting, only MS-derived LY persisted as perivascular cuffs interacting with vascular and murine immune cells, mirroring MS smoldering lesion pathology. MS LY-grafted mice exhibited impaired functional recovery and slower somatosensory evoked potential (SSEP) conduction compared to controls. Electron microscopy confirmed glial scar formation, persistent demyelination and a lesion architecture with an inflammatory inactive center but active rim. Single-nucleus RNA sequencing revealed an imbalance in CNS cell populations, with MS LY-grafted mice showing reduced neuronal abundance, enriched activated microglia, and immature oligodendroglial profiles, correlating with slower SSEP conduction speeds. Immune cell subclustering identified an enrichment of disease-associated microglia and interferon-responsive microglia in MS LY-grafted mice, marked by elevated pro-inflammatory markers and active myelin phagocytosis. Oligodendroglial cells displayed downregulated myelination and stress-response genes, with disrupted myelin ultrastructure confirmed by electron microscopy. Multiblock analysis revealed donor-specific variability, with some MS LY inducing outcomes akin to HD, while others drove severe pathology. Our model enables mechanistic dissection of the transition from focal to diffuse CNS pathology in MS and captures patient-specific pathophysiological signatures, providing a platform for personalized mechanistic studies and targeted therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/676229v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1168b07org.highwire.dtl.DTLVardef@1018361org.highwire.dtl.DTLVardef@58945eorg.highwire.dtl.DTLVardef@174b7e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's disease neurons

Parkinsons disease (PD) is characterized by -synuclein accumulation and dopaminergic neuron degeneration, with dopamine (DA) oxidation emerging as a key pathological driver. However, the mechanisms underlying this neurotoxic process remain unclear. Using PD patient-derived and CRISPR-engineered iPSC midbrain dopaminergic neurons lacking DJ-1, we identified defective sequestration of cytosolic DA into synaptic vesicles, which culminated in DA oxidation and -synuclein accumulation. In-depth proteomics, state-of-the-art imaging, and ultrasensitive DA probes uncovered that decreased VMAT2 protein and function impaired vesicular DA uptake, resulting in reduced vesicle availability and abnormal vesicle morphology. Furthermore, VMAT2 activity and vesicle endocytosis are processes dependent on ATP, which is notably reduced in DJ-1-deficient dopaminergic neurons. ATP supplementation restored vesicular function and alleviated DA-related pathologies in mutant dopaminergic neurons. This study reveals an ATP-sensitive mechanism that regulates DA homeostasis through VMAT2 and vesicle dynamics in midbrain dopaminergic neurons, highlighting enhanced DA sequestration as a promising therapeutic strategy for PD. TeaserLoss of DJ-1 interferes with VMAT2 function and vesicle dynamics, leading to DA oxidation and -synuclein pathology in PD neurons.

neuroscience↗

bioRxiv2025

A single injection of anti-PD-L1 blocking antibody induces a transient reduction in tau pathology in P301S (PS19) mouse model of tauopathy

Blocking the inhibitory PD-1/PD-L1 immune checkpoint pathway has been shown to arrest cognitive decline and reduce multiple aspects of brain pathology in various mouse models of amyloidosis and tauopathy. In this study, we evaluated whether anti-PD-L1 treatment would be effective in a tauopathy model characterized by rapidly progressing pathology. Using the P301S (PS19) transgenic mouse model, we found that a single injection of anti-PD-L1 antibody significantly attenuated cognitive deficits, with effects detectable 1-month post-treatment, aligned with the kinetics reported in other models. This cognitive benefit was observed irrespective of microglial TREM2 signalling. The effect on brain pathology was transient; phosphorylated tau in the brain, and total tau in the cerebrospinal fluid were significantly reduced 14 days post-treatment but not at 28 days. These findings indicate that PD-L1 blockade is effective across multiple disease models, while emphasizing the importance of carefully monitoring the timing of effect assessments, treatment outcomes, and dosing frequency, especially in models with accelerated disease progression.

immunology↗

bioRxiv2025

Complement activation in maternal and placental pathology of preeclampsia

Preeclampsia is a multifactorial, pregnancy-related disorder characterized by new-onset hypertension and proteinuria, with distinct early- and late-onset forms linked to varying placental and maternal pathologies. While complement system dysregulation has been implicated in the pathogenesis of preeclampsia, its causal relationship and molecular mechanisms remain unclear. In mice, complement receptor 1-related protein y (Crry) functions as a critical complement regulator at the fetal-maternal interface, essential for early embryonic survival. Complete Crry deficiency is embryonically lethal, complicating in vivo studies of complement activation in pregnancy. Using an alternative strategy, we developed a placenta-specific, doxycycline-inducible shRNA mouse model utilizing Cyp19-driven Cre recombinase and a Tet-On system to downregulate Crry in a dose-dependent manner 9.5 days post coitus, effectively restricting complement activation to the placenta. Using this model, we demonstrate that early gestation but sustained placental complement activation impairs maternal heart and liver adaptation, reduces placental efficiency, and causes fetal growth restriction, mimicking early-onset preeclampsia. Conversely, delayed complement activation induces a phenotype more consistent with late-onset preeclampsia features without placental pathology. In early-onset preeclampsia-like phenotype, the fetal growth restriction is accompanied by placental glycogen storage deficiency, and impaired hormonal function. Maternal glucose metabolism is not affected but compensatory adaptations in lipid metabolism occur although insufficient to offset fetal growth restriction. This novel model reveals that the timing of placental complement activation dictates the spectrum of preeclampsia-like pathology, providing mechanistic insights into the pathophysiology of preeclampsia.

immunology↗

bioRxiv2025

Recapitulating Parkinson's pathology in human iPSC dopaminergic neurons reveals new mechanistic insights into Lewy body formation and heterogeneity.

The accumulation of alpha-synuclein (aSyn) into intraneuronal inclusions of heterogeneous morphology, known as Lewy bodies (LB), is one of the defining diagnostic features of Parkinsons disease (PD); yet, our understanding of the mechanisms underpinning their formation and heterogeneity remains incomplete. Here, we present a human isogenic iPSC-derived dopaminergic neuron (iDA) model that faithfully recapitulates the diverse biochemical, morphological, and ultrastructural features of LB neuropathology in PD. Unlike other iDA seeding models, our model does not rely on aSyn overexpression, mutations, or genetic engineering, making it a more physiologically relevant system for studying PD. We demonstrate that the iDA model accurately reproduces the temporal relationships between neuritic and cell-body aSyn pathology, recapitulating the full biochemical spectrum, post-translational modifications (PTM), and morphological diversity of aSyn aggregates found in human PD tissue. Moreover, our work provides critical insight into how different pathways to aSyn fibrillization and the complex interaction between aSyn fibrils and membranous organelles influence the morphological diversity of LB-like inclusions. This model represents a versatile platform for investigating the mechanisms of pathology formation, maturation, and neuronal dysfunction, as well as supporting the development of diagnostics that capture the diversity of aSyn pathology in PD and related synucleinopathies.

neuroscience↗

bioRxiv2025

Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model

Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimers disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation--the pathological hallmarks of AD. While astrocytes are the primary producers of APOE in the CNS, neurons increase APOE expression under stress and aging. Prior work established that neuronal APOE4 is essential for AD pathogenesis, but whether it is sufficient to drive disease remained unknown. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons. Neuronal APOE4 alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation to levels comparable to a tauopathy model with human APOE4 knocked-in globally. Single-nucleus RNA sequencing further revealed similar transcriptomic changes in neurons and glia of both models. Together, these findings demonstrate that neuronal APOE4 alone can initiate and propagate AD pathologies, underscoring its pivotal role in disease pathogenesis and its potential as a therapeutic target.

neuroscience↗

bioRxiv2018

Comprehensive analysis of lung cancer pathology images to discover tumor shape features that predict survival outcome

Pathology slide images capture tumor histomorphological details in high resolution. However, manual detection and characterization of tumor regions in pathology slides is labor intensive and subjective. Using a deep convolutional neural network (CNN), we developed an automated tumor region recognition system for lung cancer pathology slides. From the identified regions, we extracted 22 well-defined tumor shape features and found that 15 of them were significantly associated with patient survival outcome in lung adenocarcinoma patients from the National Lung Screening Trial. A tumor shape-based prognostic model was developed and validated in an independent patient cohort (n=389). The predicted high-risk group had significantly worse survival than the low-risk group (p value = 0.0029). Predicted risk group serves as an independent prognostic factor (high-risk vs. low-risk, hazard ratio = 2.25, 95% CI 1.34-3.77, p value = 0.0022) after adjusting for age, gender, smoking status, and stage. This study provides new insights into the relationship between tumor shape and patient prognosis.

cancer biology↗

bioRxiv2018

Benfotiamine reduces pathology and improves muscle function in mdx mice.

Duchenne Muscular Dystrophy (DMD) is a progressive and fatal neuromuscular disease which arises from mutations in the dystrophin gene (DMD) that result in the absence or severe reduction of the cytoskeletal protein dystrophin. In addition to the primary dystrophin defect, secondary processes such as inflammation, calcium influx, dysregulated autophagy and fibrosis exacerbate dystrophic pathology and thus increase disease progression. While therapies to restore dystrophin deficiency are being developed, strategies which target these secondary processes could be of benefit to patients. Benfotiamine is a lipid soluble precursor to thiamine that can reduce secondary processes such as inflammation and oxidative stress in diabetic patients. As such we tested it in the mdx mouse model of DMD and found that benfotiamine reduced multiple markers of dystrophic pathology and improved grip strength. In addition, members of the utrophin and dystrophin glycoprotein complexes were significantly increased at the sarcolemma which could improve cell adhesion. We also demonstrated that benfotiamine treatment lowered the expression of macrophage markers and pro-inflammatory cytokines suggesting that benfotiamine is reducing dystrophic pathology by acting on inflammatory processes.

physiology↗

bioRxiv2018

Adaptation and inhibition control pathological synchronization in a model of focal epileptic seizure

Pharmacoresistant epilepsy is a common neurological disorder in which increased neuronal intrinsic excitability and synaptic excitation lead to pathologically synchronous behavior in the brain. In the majority of experimental and theoretical epilepsy models, epilepsy is associated with reduced inhibition in the pathological neural circuits, yet effects of intrinsic excitability are usually not explicitly analyzed. Here we present a novel neural mass model that includes intrinsic excitability in the form of spike-frequency adaptation in the excitatory population. We validated our model using local field potential data recorded from human hippocampal/subicular slices. We found that synaptic conductances and slow adaptation in the excitatory population both play essential roles for generating seizures and pre-ictal oscillations. Using bifurcation analysis, we found that transitions towards seizure and back to the resting state take place via Andronov-Hopf bifurcations. These simulations therefore suggest that single neuron adaptation as well as synaptic inhibition are responsible for orchestrating seizure dynamics and transition towards the epileptic state.\n\nSignificance statementEpileptic seizures are commonly thought to arise from a pathology of inhibition in the brain circuits. Theoretical models aiming to explain epileptic oscillations usually describe the neural activity solely in terms of inhibition and excitation. Single neuron adaptation properties are usually assumed to have only a limited contribution to seizure dynamics. To explore this issue, we developed a novel neural mass model with adaption in the excitatory population. By including adaptation and intrinsic excitability together with inhibition in this model, we were able to account for several experimentally observed properties of seizures, resting state dynamics, and pre-ictal oscillations, leading to improved understanding of epileptic seizures.

neuroscience↗

bioRxiv2018

The Time Course of Recognition Memory Impairment and Glial Pathology in the hApp-J20 Mouse Model of Alzheimer’s Disease

The role of cellular changes in the neurovascular unit is increasingly being investigated to understand the pathogenesis of Alzheimers disease. The aim of the current study was to determine the time course of recognition memory impairment in the J20 mouse model of AD, in relation to neuroinflammatory responses and the pathology of A{beta}.\n\nMale hAPP-J20 and wild-type mice were assessed at 3, 6, 9, and 12 months of age. The spontaneous object recognition (SOR) task provided a measure of memory, with assessment of both a short delay (1 min) and a long delay (4 hrs). Immunohistochemistry was used to characterise A{beta}-deposition, and quantify astrocyte and microglial responses.\n\nAt all ages tested J20 mice had impaired long-term, but preserved short-term, recognition memory. Wild-types demonstrated preserved long-term memory up to 9 months of age, and preserved short-term memory at all ages tested. Plaque pathology in the J20 mice was present from 6 months onwards, with co-localisation of reactive microglia and activated astrocytes. Reactive microglia and astrocyte activation in the hippocampus were significantly greater in the J20 mice at 9 months, compared to wild-types.\n\nThis study contributes to our understanding of the pathological and cognitive mechanisms at play in AD. J20 mice showed impairment in retaining information over longer periods from an early age, preceding the deposition of A{beta} and glial activation. Defining early physiological changes in relation to cognitive decline could provide insight into new therapeutic targets early in the disease process, when intervention is most likely to effectively slow disease progression.

neuroscience↗

bioRxiv2019

The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology

Axons are the slender, cable-like, up to meter-long projections of neurons that electrically wire our brain and body. In spite of their challenging morphology, they usually need to be maintained for an organisms lifetime. This makes them key lesion sites in pathological processes of ageing, injury and neurodegeneration. The morphology and physiology of axons crucially depends on the parallel bundles of microtubules (MTs), running all along to form their structural backbones and highways for life-sustaining cargo transport and organelle dynamics. Understanding how these bundles are formed and then maintained will provide important explanations for axon biology and pathology. Currently, much is known about MTs and the proteins that bind and regulate them, but very little about how they functionally integrate to regulate axons. As an attempt to bridge this important knowledge gap, we explain here the model of local axon homeostasis, based on our own experiments and published data. (1) As the default, we observe that axonal MTs have a strong bias to become disorganised, likely caused by the physical forces imposed by motor proteins and their life-sustaining functions during intra-axonal transport and dynamics. (2) Preventing MT disorganisation and promoting their bundled conformation, requires complex machinery involving most or even all major classes of MT-binding and - regulating proteins. As will be discussed, this model offers new explanations for axonopathies, in particular those linking to MT-regulating proteins and motors; it will hopefully motivate more researchers to study MTs, and help to decipher the complex regulatory networks that can explain axon biology and pathology.

cell biology↗

bioRxiv2019

Tau pathology in cognitively normal older adults: Associations with brain atrophy and cognitive decline

INTRODUCTIONTau pathology, a hallmark of Alzheimers disease, is observed in the brains of virtually all individuals over 70.\n\nMETHODSUsing 18F-AV-1451 (18F-flortaucipir) PET, we evaluated tau pathology in 54 cognitively normal participants (mean age 77.5, SD 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between PET signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status.\n\nRESULTSGreater age, male sex, black race, and amyloid positivity were associated with higher 18F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume ({beta} = -1.124, SE = 0.485, p = 0.025) and a steeper decline in memory performance ({beta} = -0.086, SE = 0.039, p = 0.029).\n\nDISCUSSIONAssessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimers disease.

neuroscience↗

bioRxiv2019

Computational staining of pathology images to study tumor microenvironment in lung cancer

The spatial organization of different types of cells in tumor tissues reveals important information about the tumor microenvironment (TME). In order to facilitate the study of cellular spatial organization and interactions, we developed a comprehensive nuclei segmentation and classification tool to characterize the TME from standard Hematoxylin and Eosin (H&E)-stained pathology images. This tool can computationally \"stain\" different types of cell nuclei in H&E pathology images to facilitate pathologists in analyzing the TME.\n\nA Mask Regional-Convolutional Neural Network (Mask-RCNN) model was developed to segment the nuclei of tumor, stromal, lymphocyte, macrophage, karyorrhexis and red blood cells in lung adenocarcinoma (ADC). Using this tool, we identified and classified cell nuclei and extracted 48 cell spatial organization-related features that characterize the TME. Using these features, we developed a prognostic model from the National Lung Screening Trial dataset, and independently validated the model in The Cancer Genome Atlas (TCGA) lung ADC dataset, in which the predicted high-risk group showed significantly worse survival than the low-risk group (pv= 0.001), with a hazard ratio of 2.23 [1.37-3.65] after adjusting for clinical variables. Furthermore, the image-derived TME features were significantly correlated with the gene expression of biological pathways. For example, transcription activation of both the T-cell receptor (TCR) and Programmed cell death protein 1 (PD1) pathways was positively correlated with the density of detected lymphocytes in tumor tissues, while expression of the extracellular matrix organization pathway was positively correlated with the density of stromal cells.\n\nThis study developed a deep learning-based analysis tool to dissect the TME from tumor tissue images. Using this tool, we demonstrated that the spatial organization of different cell types is predictive of patient survival and associated with the gene expression of biological pathways. Although developed from the pathology images of lung ADC, this model can be adapted into other types of cancers.

bioinformatics↗

bioRxiv2019

Proof-of-concept for the detection of early osteoarthritis pathology by endomicroscopy

Osteoarthritis (OA) is a degenerative joint disease and the leading cause of global disability. Clinical trials to date have been unable to pinpoint early and potentially reversible disease states with current clinical technology and hence disease-modifying OA drug candidates cannot be tested early in the disease. To overcome this obstacle, we correlate articular cartilage stiffness changes and cellular spatial organization. The former is a well-understood and functionally relevant OA pathology, while the latter allows discriminating between healthy vs early OA, based on distinct cellular spatial patterns. We demonstrated that an extensive loss of atomic force microscopy-detected stiffness can be seen in cartilage tissues with spatial patterns exhibiting the earliest identifiable OA. In addition, the translation of commercially available clinically usable probe-based confocal laser-endomicroscopy allows us to detect these early OA spatial patterns. This study resolves a major clinical trial obstacle by presenting the proof-of-concept that early OA pathology can be detected by already available clinical technology.\n\nOne Sentence SummaryWe report a correlation between articular cartilage surface nanoscale stiffness and chondrocyte spatial organization; using this correlation enables early pathology detection by currently available clinical optical methods.

biophysics↗

bioRxiv2019

Bayesian hierarchical models for disease mapping applied to contagious pathologies

Disease mapping aims to determine the underlying disease risk from scattered epidemiological data and to represent it on a smoothed colored map. This methodology is based on Bayesian inference and is classically dedicated to non-infectious diseases whose incidence is low and whose cases distribution is spatially (and eventually temporally) structured. Over the last decades, disease mapping has received many major improvements to extend its scope of application: integrating the temporal dimension, dealing with missing data, taking into account various a prioris (environmental and population covariates, assumptions concerning the repartition and the evolution of the risk), dealing with overdispersion, etc. We aim to adapt this approach to rare infectious diseases. In the context of a contagious disease, the outcome of a primary case can in addition generate secondary occurrences of the pathology in a close spatial and temporal neighborhood; this can result in local overdispersion and in higher spatial and temporal dependencies due to direct and/or indirect transmission. We have proposed and tested 60 Bayesian hierarchical models on 400 simulated datasets and bovine tuberculosis real data. This analysis shows the relevance of the CAR (Conditional AutoRegressive) processes to deal with the structure of the risk. We can also conclude that the negative binomial models outperform the Poisson models with a Gaussian noise to handle overdispersion. In addition our study provided relevant maps which are congruent with the real risk (simulated data) and with the knowledge concerning bovine tuberculosis (real data).\n\nAuthor summaryDisease mapping is dedicated to non-infectious diseases whose incidence is low and whose distribution is spatially (and eventually temporally) structured. In this paper, we aim to adapt this approach to rare infectious pathologies. In the context of a contagious disease, the outcome of a primary case can in addition generate secondary occurrences of the pathology in a close spatial and temporal neighborhood, resulting in local overdispersion and in high spatial and temporal dependencies. We thus explored different adapted spatial, temporal and spatiotemporal links and highlight the most adapted to likely risk structures for infectious diseases. We also conclude that the negative binomial models outperform the Poisson models with a Gaussian noise to handle overdispersion. Our study also provided relevant maps which are congruent with the real risk (in case of simulated data) and with the knowledge concerning bovine tuberculosis (when applying to real data). Thus disease mapping appears as a promising way to investigate rare infectious diseases.

scientific communication and education↗

bioRxiv2019

Optogenetic modulation of TDP-43 oligomerization fast-forwards ALS-related pathologies in the spinal motor neurons

Cytoplasmic aggregation of TDP-43 characterizes degenerating neurons in most cases of amyotrophic lateral sclerosis (ALS), yet the mechanisms and cellular outcomes of TDP-43 pathology remain largely elusive. Here, we develop an optogenetic TDP-43 variant (opTDP-43), whose multimerization status can be modulated in vivo through external light illumination. Using the translucent zebrafish neuromuscular system, we demonstrate that short-term light stimulation reversibly induces cytoplasmic opTDP-43 mislocalization, but not aggregation, in the spinal motor neuron, leading to an axon outgrowth defect associated with myofiber denervation. In contrast, opTDP-43 forms pathological aggregates in the cytoplasm after longer-term illumination and seeds non-optogenetic TDP-43 aggregation. Furthermore, we find that an ALS-linked mutation in the intrinsically disordered region (IDR) exacerbates the light-dependent opTDP-43 toxicity on locomotor behavior. Together, our results propose that IDR-mediated TDP-43 oligomerization triggers both acute and long-term pathologies of motor neurons, which may be relevant to the pathogenesis and progression of ALS.

neuroscience↗

bioRxiv2019

ZIKA VIRUS INFECTION DURING PREGNANCY AND INDUCED BRAIN PATHOLOGY IN BECLIN1-DEFICIENT MOUSE MODEL

We investigated the role of the autophagy protein, Beclin1, in the replication and disease of Zika virus (ZIKV) in pregnant dams and their offspring using Beclin1-deficient (Atg6+/-) and wild-type (Atg6+/+) mouse model infected with the Honduran (R103451), Puerto Rican (PRVABC59), and the Uganda (MR766) strains of ZIKV. Pregnant dams infected subcutaneously at embryonic stage (E)9 showed viral RNA in serum harvested at E13 and in various organs removed postmortem at E17. Subcutaneous infections with ZIKV also showed the vertical transmission of ZIKV from the placenta to embryos removed postmortem at E17. From the three isolates, R103451-infected Atg6+/- dams had the lowest mortality rate while 30 % of their offspring containing the hemizygous beclin1 allele (Atg6+/-) were smaller in size and had smaller and underdeveloped brain. Growth impairment in the pups became noticeable after two weeks post-birth. After 21-days, pups were sacrificed and brain tissues removed postmortem showed expression of the envelope (E) and the non-structural (NS)-1 proteins, along with signs of neuronal injury, despite an absence in viral RNA detection. A significant decrease in the mRNA expression levels of the insulin-like growth factor-1 (IGF-1) by 8-fold and a decrease in the mRNA expression levels of several microcephaly related genes along with an increase in the secretion of several inflammatory molecules may have contributed to the observed phenotype. Since autophagy regulates cytokines and chemokines production, a dysregulation in this pathway may have further exacerbated the pathology of ZIKV. IMPORTANCEPups delivered from ZIKV-infected dams showed significant growth impairments in the body and the brain. We believe that the reduction in insulin growth factor together with the increase secretion of inflammatory molecules may have triggered neuronal injury and the downregulation of the microcephalic genes, while reduced expression of the autophagy protein, Beclin1 further exacerbated the pathology. Although the mechanism is still unknown, the autophagy pathway seems to play a key role in ZIKV pathology. It is therefore of great significance to study the role of autophagy during viral infection with the goal to identify potential targets for anti-ZIKV therapeutic intervention.

immunology↗